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34 gesichtete, geschützte Fragmente: Plagiat

[1.] Vpr/Fragment 002 07 - Diskussion
Bearbeitet: 17. March 2014, 12:28 Graf Isolan
Erstellt: 13. March 2014, 23:42 (Hindemith)
Fragment, Gesichtet, KomplettPlagiat, Lessard et al 2004, SMWFragment, Schutzlevel sysop, Vpr

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Seite: 2, Zeilen: 7-11
Quelle: Lessard_et_al_2004
Seite(n): 7199, Zeilen: l.col: 23-29
The first evidence for the existence of such a cell-type came from experiments by Ray Owen and co-workers in 1945, which showed that bovine fraternal twins, sharing a single placenta and blood circulation, retained production of blood cells genetically defined to be from both throughout their life. The first evidence for the existence of such a cell-type came from experiments by Ray Owen and co-workers, in 1945, which showed that bovine fraternal twins, sharing a single placenta and blood circulation, retained production of blood cells genetically defined to be from both throughout their life (Owen, 1945).
Anmerkungen

The source is not mentioned anywhere in the thesis.

Sichter
(Hindemith) Schumann

[2.] Vpr/Fragment 002 19 - Diskussion
Bearbeitet: 17. March 2014, 12:29 Graf Isolan
Erstellt: 13. March 2014, 23:47 (Hindemith)
Fragment, Gesichtet, Lessard et al 2004, SMWFragment, Schutzlevel sysop, Verschleierung, Vpr

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Untersuchte Arbeit:
Seite: 2, Zeilen: 19-25
Quelle: Lessard_et_al_2004
Seite(n): 7199, Zeilen: r.col: 31-39
The first attempts at purifying HSCs came from experiments carried out by Till and McCullogh in the Netherlands (Van Bekkum et. al., 1979; Worton et. al., 1969). Based on their work, it has become possible to routinely identify and isolate highly purified murine and human HSCs based mainly on characteristic cell surface proteins that are either present (Sca1 and c-kit) or absent (using markers of lineage committed cells such as CD38, Mac-1 and CD8) (Weissman, 2002).

Van Bekkum, D. W., van den Engh, G. J., Wagemaker, G., Bol, S. J., and Visser, J. W. (1979).
Structural identity of the pluripotential hemopoietic stem cell. Blood Cells 5, 143-159.

Weissman, I. L. (2002).
The road ended up at stem cells. Immunol Rev 185, 159-174.

Worton, R. G., McCulloch, E. A., and Till, J. E. (1969).
Physical separation of hemopoietic stem cells differing in their capacity for self-renewal. J Exp Med 130, 91-103.

The first attempts at purifying the HSC came from experiments carried out by Till and McCullogh (Worton et al., 1969; van Bekkum et al., 1979) in the Netherlands. From this work, it has become possible to routinely identify and isolate highly purified murine and human HSCs based mainly on characteristic cell surface proteins that are either present (Sca-1 and c-kit) or absent (using markers of lineage committed cells such as CD38, Mac-1 and CD8) (reviewed in Weissman, 2002).

van Bekkum DW, van den Engh GJ, Wagemaker G, Bol SJ and Visser JW. (1979). Blood Cells, 5, 143–159.

Weissman IL. (2002). Immunol. Rev., 185, 159–174.

Worton RG, McCulloch EA and Till JE. (1969). J. Exp. Med., 130, 91–103.

Anmerkungen

The source is not mentioned anywhere in the thesis.

Sichter
(Hindemith) Schumann

[3.] Vpr/Fragment 002 26 - Diskussion
Bearbeitet: 17. March 2014, 12:28 Graf Isolan
Erstellt: 12. March 2014, 22:34 (Hindemith)
Fragment, Gesichtet, Reya et al 2001, SMWFragment, Schutzlevel sysop, Verschleierung, Vpr

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Quelle: Reya et al 2001
Seite(n): 105, Zeilen: r.col: 23-31
In the hematopoietic system, stem cells are heterogeneous with respect to their ability to self-renew and can be divided into three different populations: long-term self-renewing HSCs, short-term self-renewing HSCs, and multipotent progenitors without detectable self-renewal potential (Morrison and Weissman, 1994; Morrison et. al., 1997). These populations form a lineage in which the long-term HSCs give rise to short-term HSCs, which in turn give rise to multi-[potent progenitors (Morrison et. al., 1997).]

Morrison, S. J., Wandycz, A. M., Hemmati, H. D., Wright, D. E., and Weissman, I. L. (1997). Identification of a lineage of multipotent hematopoietic progenitors. Development 124, 1929-1939.

Morrison, S. J., and Weissman, I. L. (1994). The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1, 661-673.

In the haematopoietic system, stem cells are heterogeneous with respect to their ability to self-renew. Multipotent progenitors constitute 0.05% of mouse bone-marrow cells, and can be divided into three different populations: long-term self-renewing HSCs, short-term self-renewing HSCs, and multipotent progenitors without detectable self-renewal potential2,11. These populations form a lineage in which the long-term HSCs give rise to short-term HSCs, which in turn give rise to multipotent progenitors11.

2. Morrison, S. J. & Weissman, I. L. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1, 661–673 (1994).

11. Morrison, S. J., Wandycz, A. M., Hemmati, H. D., Wright, D. E. & Weissman, I. L. Identification of a lineage of multipotent hematopoietic progenitors. Development 124, 1929–1939 (1997).

Anmerkungen

The source is not mentioned here.

On the next page the copied text continues.

Sichter
(Hindemith) Schumann

[4.] Vpr/Fragment 003 01 - Diskussion
Bearbeitet: 16. March 2014, 23:25 Hindemith
Erstellt: 12. March 2014, 22:46 (Hindemith)
BauernOpfer, Fragment, Gesichtet, Reya et al 2001, SMWFragment, Schutzlevel sysop, Vpr

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Seite: 3, Zeilen: 1-6
Quelle: Reya et al 2001
Seite(n): 105, 106, Zeilen: 105: r.col: 31-37; 106: figure
As HSCs mature from the long-term self-renewing pool to multipotent progenitors, they progressively lose their potential to self-renew but become more mitotically active. Whereas long-term HSCs give rise to mature hematopoietic cells for the lifetime of the mouse, short-term HSCs and multipotent progenitors reconstitute lethally irradiated mice for less than eight weeks (Fig.2).

03a diss Vpr.png

Figure 2. Development of hematopoietic stem cells. HSCs can be subdivided into long-term self-renewing HSCs, short-term self-renewing HSCs and multipotent progenitors (red arrows indicate self-renewal). They give rise to common lymphoid progenitors (CLPs) and common myeloid progenitors (CMPs). Both CMPs/GMPs (granulocyte macrophage precursors) and CLPs can give rise to all known mouse hematopoietic cells (Figure adapted from Reya et. al., 2001)

[page 105]

As HSCs mature from the long-term self-renewing pool to multipotent progenitors, they progressively lose their potential to self-renew but become more mitotically active. Whereas long-term HSCs give rise to mature haematopoietic cells for the lifetime of the mouse, short-term HSCs and multipotent progenitors reconstitute lethally irradiated mice for less than eight weeks.

[page 106]

03a source Vpr.png

Development of haematopoietic stem cells. HSCs can be subdivided into long-term self-renewing HSCs, short-term self-renewing HSCs and multipotent progenitors (red arrows indicate self-renewal). They give rise to common lymphoid progenitors (CLPs; the precursors of all lymphoid cells) and common myeloid progenitors (CMPs; the precursors of all myeloid cells). Both CMPs/GMPs (granulocyte macrophage precursors) and CLPs can give rise to all known mouse dendritic cells.

Anmerkungen

The source is given, but only for the figure: "Figure adapted from Reya et. al., 2001" It is not clear to the reader that the text before the figure is also taken from this source, that the figure has not been "adapted" but copied and that also the figure caption is taken from the source.

Sichter
(Hindemith) Schumann

[5.] Vpr/Fragment 004 10 - Diskussion
Bearbeitet: 4. April 2014, 23:00 Hindemith
Erstellt: 12. March 2014, 21:32 (Hindemith)
BauernOpfer, Fragment, Gesichtet, Jamieson et al 2004, SMWFragment, Schutzlevel sysop, Vpr

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Quelle: Jamieson et al 2004
Seite(n): 531, Zeilen: col 1: 1-11
Human cancer stem cells, identified in acute myelogenous leukemia (AML) (Bonnet and Dick, 1997), myeloid blast crisis of chronic myelogenous leukemia (Jamieson et. al., 2004), breast cancer and brain tumors (Al-Hajj et. al., 2003; Singh et. al., 2003) share functional properties with normal stem cells such as self-renewal, high proliferative potential, some differentiation capacity and ability to be serially transplanted (Jamieson et. al., 2004b; Passegue et. al., 2003).

Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J., and Clarke, M. F. (2003). Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100, 3983-3988.

Bonnet, D., and Dick, J. E. (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3, 730-737.

Jamieson, C. H., Ailles, L. E., Dylla, S. J., Muijtjens, M., Jones, C., Zehnder, J. L., Gotlib, J., Li, K., Manz, M. G., Keating, A., et al. (2004a). Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 351, 657- 667.

Jamieson, C. H., Weissman, I. L., and Passegue, E. (2004b). Chronic versus acute myelogenous leukemia; A question of self-renewal. Cancer Cell 6, 531-533.

Passegue, E., Jamieson, C. H., Ailles, L. E., and Weissman, I. L. (2003). Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci U S A 100 Suppl 1, 11842-11849.

Singh, S. K., Clarke, I. D., Terasaki, M., Bonn, V. E., Hawkins, C., Squire, J., and Dirks, P. B. (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63, 5821-5828.

Human cancer stem cells, identified in acute myelogenous leukemia (Bonnet and Dick, 1997), myeloid blast crisis of chronic myelogenous leukemia (Jamieson et al, 2004), breast cancer (Al-Hajj et al., 2003), and brain tumors (Singh et al., 2003), share functional properties with normal stem cells, such as high proliferative potential, some differentiation capacity, and the ability to be serially transplanted (reviewed in Passegué et al., 2003).

Al-Hajj, M., Wicha, M., Benito-Hernandez, A., Morrison, S., and Clarke, M. (2003). Proc. Natl. Acad. Sci. USA 100, 3983–3988.

Bonnet, D., and Dick, J.E. (1997). Nat. Med. 3, 730–737.

Jamieson, C.H., Ailles, L.E., Dylla, S.J., Muijtjens, M., Jones, C., Zehnder, J.L., Gotlib, J., Li, K., Manz, M.G., Keating, A., et al. (2004). N. Engl. J. Med. 351, 657–667.

Passegué, E., Jamieson, C.H.M., Ailles, L.E., and Weissman, I.L. (2003). Proc. Natl. Acad. Sci. USA 100, 11842–11849.

Singh, S.K., Clarke, I.D., Terasaki, M., Bonn, V.E., Hawkins, C., Squire, J., and Dirks, P.B. (2003). Cancer Res. 63, 5821–5828.

Anmerkungen

The source is mentioned, but it is not clear that the overview of the literature is taken from it. The reader rather assumes that the given source is just one more reference.

Sichter
(Hindemith) Schumann

[6.] Vpr/Fragment 004 23 - Diskussion
Bearbeitet: 17. March 2014, 12:35 Graf Isolan
Erstellt: 11. March 2014, 20:31 (SleepyHollow02)
BauernOpfer, Fragment, Gesichtet, Reya et al 2001, SMWFragment, Schutzlevel sysop, Vpr

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Seite: 4, Zeilen: 23-31
Quelle: Reya et al 2001
Seite(n): 107, Zeilen: left col., 23-28 - right col. 1-7
If dysregulation of signaling pathways that normally regulate stem cell selfrenewal leads to tumorigenesis, then stem cells themselves might be the target of transformation in certain types of cancer. There are two reasons to think that this hypothesis may be correct: first, because stem cells have the machinery for self-renewal already activated, maintaining this activation may be simpler than turning it on de novo in a more differentiated cell; that is, fewer mutations may be required to maintain self-renewal than to activate it ectopically. Secondly, stem cells often persist for long periods of time, instead of dying like many mature cells in highly proliferative tissues. This means that there is a much greater [opportunity for mutations to accumulate in individual stem cells than in most mature cell types.] If the signalling pathways that normally regulate stem cell selfrenewal lead to tumorigenesis when dysregulated, then are stem cells themselves the target of transformation in certain types of cancer28,29? There are two reasons to think that this may be the case. First, because stem cells have the machinery for self-renewal already activated, maintaining this activation may be simpler than turning it on de novo in a more differentiated cell; that is, fewer mutations may be required to maintain self-renewal than to activate it ectopically. Second, by self-renewing, stem cells often persist for long periods of time, instead of dying after short periods of time like many mature cells in highly proliferative tissues. This means that there is a much greater opportunity for mutations to accumulate in individual stem cells than in most mature cell types (Fig. 3).
Anmerkungen

The source is mentioned two sentences further down, but it is not clear that Reya et al are quoted literally here.

Sichter
(SleepyHollow02) Schumann

[7.] Vpr/Fragment 005 09 - Diskussion
Bearbeitet: 4. April 2014, 23:00 Hindemith
Erstellt: 12. March 2014, 21:40 (Hindemith)
BauernOpfer, Fragment, Gesichtet, Jamieson et al 2004, SMWFragment, Schutzlevel sysop, Vpr

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Seite: 5, Zeilen: 9-22
Quelle: Jamieson et al 2004
Seite(n): 532, Zeilen: figure
05a diss Vpr.png

Figure 3. Oncogene hierarchy and role of self-renewal in the pathogenesis of leukemias.

A. Normal myelopoiesis is distinguished by the orderly differentiation of HSC, which are the only cells with self-renewal capacity, into committed myeloid progenitors and their respective terminally differentiated progeny. B. Chronic diseases, such as chronic phase CML, are associated with preleukemic events that result in increased survival and proliferation within the stem and myeloid progenitor populations but continued production of terminally differentiated progeny. Acquisition of BCR-ABL, overexpression of BCL2, and inactivation of JunB expression are examples of such events that initially take place in HSC. C and D: Acute diseases such as blast crisis CML and AML are marked by acquisition of self-renewal capacity by progenitors that normally lack it or by enhanced self-renewal in HSC. β-catenin activation during the progression of CML to blast crisis is an example of such a leukemogenic event occurring in myeloid progenitors. MOZ-TIF2 and MLL-ENL are AML-associated translocation products that may enhance HSC self-renewal or endow myeloid progenitors with self-renewal potential. Together with a subsequent block in differentiation, these leukemogenic [events result in the accumulation of immature blast progeny and development of AML at either the HSC or myeloid progenitor stage (Figure adapted from Jamieson et. al., 2004b) .]

05a source Vpr.png

Figure 1. Oncogene hierarchy and role of self-renewal in pathogenesis of leukemias

A: Normal myelopoiesis is distinguished by the orderly differentiation of hematopoietic stem cells (HSC), which are the only cells with self-renewal capacity, into committed myeloid progenitors and their respective terminally differentiated progeny.

B: Chronic diseases, such as chronic phase CML, are associated with preleukemic events that result in increased survival and proliferation within the stem and myeloid progenitor populations but continued production of terminally differentiated progeny. Acquisition of BCR-ABL, overexpression of Bcl2, and inactivation of JunB expression are examples of such events that initially take place in HSC.

C and D: Acute diseases such as blast crisis CML and AML are marked by acquisition of self-renewal capacity by progenitors that normally lack it or by enhanced self-renewal in HSC. β-catenin activation during the progression of CML to blast crisis is an example of such a leukemogenic event occurring in myeloid progenitors. MOZ-TIF2 and MLL-ENL are AML-associated translocation products that may enhance HSC self-renewal or endow myeloid progenitors with self-renewal potential. Together with a subsequent block in differentiation, these leukemogenic events result in the accumulation of immature blast progeny and development of AML at either the HSC or myeloid progenitor stage.

Anmerkungen

The source is mentioned: "Figure adapted from Jamieson et. al., 2004b", but is not clear to the reader that "adapted from" actually means "copied from" and that also the very extensive figure caption has been copied 1-to-1.

Sichter
(Hindemith) Schumann

[8.] Vpr/Fragment 006 16 - Diskussion
Bearbeitet: 5. April 2014, 07:37 Hindemith
Erstellt: 13. March 2014, 08:29 (Hindemith)
BauernOpfer, Fragment, Gesichtet, Owens and Hawley 2002, SMWFragment, Schutzlevel sysop, Vpr

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Quelle: Owens and Hawley 2002
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Sequences flanking the HD also influence specificity by coordinating interaction with cofactor proteins that influence DNA-binding properties. Homeobox genes are divided into two classes. [...] (Abate-Shen, 2002; Owens and Hawley, 2002) Sequences flanking the HD also influence specificity by coordinating interaction with cofactor proteins that influence DNA-binding properties.

HD encoding (homeobox [HB]) genes are broadly divided into two classes.

Anmerkungen

The source is mentioned two sentences further down, but it is not clear that this reference applies to the here documented sentence, and it is also not clear that Owens and Hawley are quoted literally here.

Sichter
(Hindemith) Schumann

[9.] Vpr/Fragment 007 01 - Diskussion
Bearbeitet: 5. April 2014, 07:38 Hindemith
Erstellt: 13. March 2014, 21:47 (Hindemith)
Abate-Shen 2002, BauernOpfer, Fragment, Gesichtet, SMWFragment, Schutzlevel sysop, Vpr

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Quelle: Abate-Shen 2002
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07a diss Vpr.png

Figure 4. The structure of the homeodomain. Despite its considerable variation in primary sequence, the three-dimensional structure of the homeodomain has been well conserved, and corresponds to three α helices that have a relatively unstructured amino-terminal arm. The consensus amino acids, which are invariant among all homeodomains, are essential in maintaining structural integrity and making essential contacts with DNA. Amino acids that distinguish the various homeoprotein families contribute to differences in their DNA-binding specificities and other functional properties. The figure shows the Engrailed–DNA complex (Figure adapted from Abate-Shen, 2002)

07b diss Vpr.png

Figure 5. Generating diversity among homeoproteins. The distinct classes of homeoproteins show considerable sequence diversity within the homeodomain (top), and within the amino- and carboxy-terminal regions that flank this domain (bottom). The sequence diversity is believed to contribute to their distinct functional properties, by generating distinct DNA-binding specificities, promoting unique protein–protein interactions, and other mechanisms. [Functional diversity is also generated by additional conserved domains or motifs that occur in particular homeoprotein families. HOX proteins contain a hexapeptide (HP) motif-a short stretch of conserved residues that are responsible for mediating interactions with PBX homeoproteins. MSX proteins also have short stretches of conserved amino acids that flank the homeodomain, called the extended homeodomain (EHD), although their functions are unknown. PAX proteins contain an additional DNA-binding domain, known as the paired box. Members of the SIX family have a conserved amino-terminal domain called the Six domain, and LIM homeoproteins are named after a protein interaction motif, the LIM domain (Figure adapted from Abate-Shen, 2002).]

Box 3 Generating diversity among homeoproteins

The distinct classes of homeoproteins show considerable sequence diversity within the homeodomains (top), and within the amino- and carboxy-terminal regions that flank this domain (bottom). The sequence diversity is believed to contribute to their distinct functional properties, by generating distinct DNA-binding specificities, promoting unique protein–protein interactions, and other mechanisms. Functional diversity is also generated by additional conserved domains or motifs that occur in particular homeoprotein families. HOX proteins contain a hexapeptide (HP) motif-a short stretch of conserved residues that are responsible for mediating interactions with PBX homeoproteins. MSX proteins also have short stretches of conserved amino acids that flank the homeodomain, called the extended homeodomain (EHD), although their functions are unknown. PAX proteins contain an additional DNA-binding domain, known as the paired box. Members of the SIX family have a conserved amino-terminal domain called the Six domain, and LIM homeoproteins are named after the protein interaction motif, the LIM domain.

07b source Vpr.png


Box 4 The structure of the homeodomain

Despite its considerable variation in primary sequence, the three-dimensional structure of the homeodomain has been well conserved, and corresponds to three α-helices that have a relatively unstructured amino-terminal arm. The consensus amino acids, which are invariant among all homeodomains, are essential in maintaining structural integrity and making essential contacts with DNA. Amino acids that distinguish the various homeoprotein families contribute to differences in their DNA-binding specificities and other functional properties. The figure shows the Engrailed–DNA complex.

07a source Vpr.png

Anmerkungen

The source is given at the end of the two figure captions. However, both figures are copied and not "adapted". Furthermore, the extensive figure captions are also taken 1-to-1 from the source, which does not become clear from the references at all.

Sichter
(Hindemith) Schumann

[10.] Vpr/Fragment 008 01 - Diskussion
Bearbeitet: 5. April 2014, 07:38 Hindemith
Erstellt: 13. March 2014, 21:56 (Hindemith)
Abate-Shen 2002, BauernOpfer, Fragment, Gesichtet, SMWFragment, Schutzlevel sysop, Vpr

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Functional diversity is also generated by additional conserved domains or motifs that occur in particular homeoprotein families. HOX proteins contain a hexapeptide (HP) motif-a short stretch of conserved residues that are responsible for mediating interactions with PBX homeoproteins. MSX proteins also have short stretches of conserved amino acids that flank the homeodomain, called the extended homeodomain (EHD), although their functions are unknown. PAX proteins contain an additional DNA-binding domain, known as the paired box. Members of the SIX family have a conserved amino-terminal domain called the Six domain, and LIM homeoproteins are named after a protein interaction motif, the LIM domain (Figure adapted from Abate-Shen, 2002). Functional diversity is also generated by additional conserved domains or motifs that occur in particular homeoprotein families. HOX proteins contain a hexapeptide (HP) motif-a short stretch of conserved residues that are responsible for mediating interactions with PBX homeoproteins. MSX proteins also have short stretches of conserved amino acids that flank the homeodomain, called the extended homeodomain (EHD), although their functions are unknown. PAX proteins contain an additional DNA-binding domain, known as the paired box. Members of the SIX family have a conserved amino-terminal domain called the Six domain, and LIM homeoproteins are named after the protein interaction motif, the LIM domain.
Anmerkungen

The copied text belongs to a figure caption, see Vpr/Fragment_007_01.

The source is given, but the reference only covers the figure, not the equally copied figure caption.

Sichter
(Hindemith) Schumann

[11.] Vpr/Fragment 008 27 - Diskussion
Bearbeitet: 5. April 2014, 07:41 Hindemith
Erstellt: 13. March 2014, 08:32 (Hindemith)
Fragment, Gesichtet, KomplettPlagiat, Owens and Hawley 2002, SMWFragment, Schutzlevel sysop, Vpr

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The function of HOX genes in hematopoiesis has been investigated through knockout mouse models and overexpression from retroviral vectors in hematopoietic stem cells from murine fetal liver and bone marrow and in human cord blood progenitors. The function of HOX genes in hematopoiesis has been investigated through knockout mouse models and enforced overexpression from retroviral vectors in hematopoietic stem cells from murine fetal liver and bone marrow and in human cord blood progenitors.
Anmerkungen

The source is not mentioned.

Sichter
(Hindemith) Schumann

[12.] Vpr/Fragment 009 01 - Diskussion
Bearbeitet: 5. April 2014, 19:39 Hindemith
Erstellt: 13. March 2014, 07:50 (Hindemith)
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Seite(n): 2286, 2287, Zeilen: 2286:1f., l.col: 8-17; 2287: l.col: 8-11
Leukemic blasts from many patients with acute myeloid leukemia (AML) show an aberrant pattern of HOXA10 expression, further supporting the concept that dysregulated HOX gene expression may be a general feature of this malignancy (Kawagoe et. al., 1999; Lawrence et. al., 1995). Overexpression of HOXA10 in the progeny of human cord blood or fetal liver cells perturbs human lymphomyelopoiesis in vitro and in vivo (Buske et. al., 2001). Notably, the expression of HOXA9 has been identified as one of the most consistent diagnostic markers of AML in humans and as the only single gene expression marker of more than 6800 cDNAs tested by DNA micro-array analysis that correlated with clinical outcome (Golub et. al., 1999).

Buske, C., Feuring-Buske, M., Antonchuk, J., Rosten, P., Hogge, D. E., Eaves, C. J., and Humphries, R. K. (2001). Overexpression of HOXA10 perturbs human lymphomyelopoiesis in vitro and in vivo. Blood 97, 2286-2292.

Golub, T. R., Slonim, D. K., Tamayo, P., Huard, C., Gaasenbeek, M., Mesirov, J. P., Coller, H., Loh, M. L., Downing, J. R., Caligiuri, M. A., et al. (1999a). Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286, 531-537.

Kawagoe, H., Humphries, R. K., Blair, A., Sutherland, H. J., and Hogge, D. E. (1999). Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells. Leukemia 13, 687-698.

Lawrence, H. J., Sauvageau, G., Ahmadi, N., Lopez, A. R., LeBeau, M. M., Link, M., Humphries, K., and Largman, C. (1995). Stage- and lineage-specific expression of the HOXA10 homeobox gene in normal and leukemic hematopoietic cells. Exp Hematol 23, 1160-1166.

Overexpression of HOXA10 perturbs human lymphomyelopoiesis in vitro and in vivo

[...]

[...] More recently, we and others have shown that the leukemic blasts from many patients with acute myeloid leukemia (AML) show an aberrant pattern of HOXA10 expression, further supporting the concept that dysregulated HOX gene expression may be a general feature of this malignancy.8,9 Notably, the expression of HOXA9 has been identified as one of the most consistent diagnostic markers of AML in humans and as the only single gene expression marker of more than 6800 cDNAs tested by DNA micro-array analysis that correlated with clinical outcome.10

[page 2287]

We focused on the analysis of the effects of HOXA10 overexpression in the progeny of human cord blood or fetal liver cells [...]


8. Lawrence HJ, Sauvageau G, Ahmadi N, et al. Stage- and lineage-specific expression of the HOXA10 homeobox gene in normal and leukemic hematopoietic cells. Exp Hematol. 1995;23:1160- 1166.

9. Kawagoe H, Humphries RK, Blair A, Sutherland HJ, Hogge DE. Expression of HOX genes, Hoxcofactors, and Mll in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells. Leukemia.1999; 13:687-698.

10. Golub TR, Slonim DK, Tamayo P, et al. Molecular classification of cancer: class discovery and class prediction by gene expressing monitoring. Science. 1999;286:531-537.

Anmerkungen

The source is mentioned, but the copied text continues after the reference to Buske and in the way the reference is given the reader must assume it is given only for the statement "Overexpression of HOXA10 in the progeny of human cord blood or fetal liver cells perturbs human lymphomyelopoiesis in vitro and in vivo".

Sichter
(Hindemith) Schumann

[13.] Vpr/Fragment 010 09 - Diskussion
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1.3.2 Non-clustered homeobox genes in leukemogenesis

Several non-clustered HD proteins have been shown to function as cofactors for HOX proteins, interacting with HOX genes by a conserved sequence YPWMK and are co-expressed during embryonic development. These include the three-amino-acid-loop-extension (TALE) proteins, PBX, MEIS, and PREP1/KNOX1. PBX genes are widely expressed in fetal and adult tissues, although PBX1 transcripts are notably absent from lymphocytes (Monica et. al., 1991). The hematopoietically expressed (HEX) gene as another example of a non-clustered homeobox gene was initially identified in human hematopoietic cells, where it is expressed in multipotential progenitors, myeloid cells, and B cells, but not T or erythroid cells (Bedford et. al., 1993). HEX expression has also been detected in peripheral blood leukocytes from leukemia patients (Manfioletti et. al., 1995). Other non-HOX HB genes like HOX11, and members of the CDX, HLX, and PMX1 families are more restricted in their patterns of expression, and are involved in organogenesis or differentiation of specific cell types.

[page 365]

Several non-HOX HD proteins have been shown to function as cofactors for HOX proteins and are cosynthesized during embryonic development. These include the three-amino-acid-loop-extension (TALE) proteins, PBX, MEIS, and PREP1/KNOX1. PBX genes are widely expressed in fetal and adult tissues, although PBX1 transcripts are notably absent from lymphocytes [28]. [...]

Other non-HOX HB genes are more restricted in their patterns of expression, and their encoded HD proteins are involved in organogenesis or differentiation of specific cell types.

[page 371]

HEX (hematopoietically expressed HB; Hhex/Prh) was initially identified in human hematopoietic cells, where it is expressed in multipotential progenitors, myeloid cells, and B cells, but not T or erythroid cells [127]. HEX expression has also been detected in peripheral blood leukocytes from leukemia patients [127, 128]


28 Monica K, Galili N, Nourse J et al. PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1. Mol Cell Biol 1991;11:6149-6157.

127 Bedford FK, Ashworth A, Enver T et al. HEX: a novel homeobox gene expressed during haematopoiesis and conserved between mouse and human. Nucleic Acids Res 1993;21:1245-1249.

128 Manfioletti G, Gattei V, Buratti E et al. Differential expression of a novel proline-rich homeobox gene (Prh) in human hematolymphopoietic cells. Blood 1995;85:1237-1245.

Anmerkungen

The only reference to the source is made on p.6.

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(SleepyHollow02) Schumann

[14.] Vpr/Fragment 011 01 - Diskussion
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1.3.2.1 TALE homeobox genes

Members of the TALE family of non-HOX HD cofactor proteins, which include PBX, MEIS, and PREP1/KNOX1 proteins, are distinguished from other HD proteins by the inclusion of an additional three amino acids between α- helices 1 and 2 within the HD. Evidence from mouse models and human leukemic cells has indicated that inappropriate expression of TALE cofactors with certain HD proteins may contribute to leukemic transformation, while overexpression of TALE cofactors alone does not lead to disease development. One of these proteins, PBX1, has oncogenic potential in the form of a fusion protein with E2A. The PBX1 gene was originally identified at the breakpoint of the t(1;19) translocation found in 10 to 20% of childhood pre-B-cell ALL (Shikano et. al., 1999).

Members of the TALE family of non-HOX HD cofactor proteins, which include PBX, MEIS, and PREP1/KNOX1 proteins, are distinguished from other HD proteins by the inclusion of an additional three amino acids between α-helices 1 and 2 within the HD. Evidence from mouse models and human leukemic cells has indicated that inappropriate expression of TALE cofactors with certain HD proteins may contribute to leukemic transformation, while overexpression of TALE cofactors alone does not lead to disease development. However, as noted above and discussed in detail below, one of these proteins, PBX1, has oncogenic potential in the form of a fusion protein with E2A. The PBX1 gene was originally identified at the breakpoint of the t(1;19) translocation found in childhood pre-B-cell ALL [29, 30]

29 Kamps MP, Murre C, Sun XH et al. A new homeobox gene contributes the DNA binding domain of the t(1;19) translocation protein in pre-B ALL. Cell 1990;60:547-555.

30 Nourse J, Mellentin JD, Galili N et al. Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor. Cell 1990;60:535-545.

Anmerkungen

The source is not mentioned.

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(SleepyHollow02) Schumann

[15.] Vpr/Fragment 012 06 - Diskussion
Bearbeitet: 17. March 2014, 12:29 Graf Isolan
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Cdx2 expression starts in the proximal intestine and decreases posteriorly, whereas Cdx1 expression starts in the distal intestine with overlapping expression of Cdx1 and Cdx2 in the midgut (Fig.8).

12a diss Vpr.png

Figure 8. Regional expression of transcription factors in the developing gut. The transcription factors shown on the right have been mapped to specific regions of the endoderm, as shown on the left. There is a presumed rule of expression patterns of HOX genes in the developing gut. Each subdomain of the developing digestive tract (foregut, midgut and hindgut) seems to have a different HOX code: Cdx2 expression starts in the proximal intestine and decreases (lightening bar) posteriorly, whereas Cdx1 expression starts in the distal intestine and decreases anteriorly. Pdx1 expression has been observed in the antrum and duodenum. Sox2 is expressed from the pharynx to the stomach.

[page 593]

CDX2 expression starts in the proximal intestine and decreases posteriorly, whereas CDX1 expression starts in the distal intestine, and they overlap in the midgut.

[page 594]

12a source Vpr.png

Figure 2 Regional expression of transcription factors in the developing gut. The transcription factors shown on the right have been mapped to specific regions of the endoderm, as shown on the left. There is a presumed rule of expression patterns of HOX genes in the developing gut. Each subdomain of the developing digestive tract (foregut, midgut and hindgut) seems to have a different HOX code8,12,13. CDX2 expression starts in the proximal intestine and decreases (lightening bar) posteriorly, whereas CDX1 expression starts in the distal intestine and decreases anteriorly16. PDX1 expression has been observed in the antrum and duodenum17. SOX2 is expressed from the pharynx to the stomach27.


[...]

Anmerkungen

The source is nowhere mentioned in the thesis.

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(Hindemith) Schumann

[16.] Vpr/Fragment 014 01 - Diskussion
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1.4.1 Role of Cdx2 in embryogenesis and intestine development

Cdx genes have developmental roles and overlap in their expression patterns. Cdx2 is expressed at 3.5 days postcoitum (dpc) in the trophectoderm but not in the inner cell mass (Beck et. al., 1995). At 7.5 dpc (Theiler stage 11), it is present in the chorion, ectoplacental cone, mesoderm of the developing allantoic bud, and posterior primitive streak. At 8.5 dpc (Theiler stage 13), expression is seen in all three germ layers at the posterior end of the embryo extending into the mesodermal root of the allantois, in the endodermal epithelium of the hindgut rudiment, and in the neural tube; the presegmented paraxial mesoderm expresses the gene, but the somites, lateral plate, and intermediate mesoderm do not. By 9.5 dpc (Theiler stage 15), the caudal pole of the embryo remains positive, as does the posterior neural tube and posterior gut endoderm. At 12.5 dpc (Theiler stage 20), expression is confined exclusively to the gut endoderm posterior to the foregut-midgut junction (Beck et. al., 1995; Chawengsaksophak et. al., 2004). Cdx1 expression extends most anteriorly, followed by Cdx2 and Cdx4, with all three genes expressed posteriorly.

Cdx2-null mutant embryos die between 3.5 and 5.5 dpc, and heterozygotes have tail abnormalities and exhibit anterior homeotic transformations involving the cervical and upper thoracic vertebrae, ribs, and midgut endoderm. [90% of Cdx2 heterozygote mutant mice develop multiple intestinal adenomatous polyps, particularly in the proximal colon, suggesting that Cdx2 mutations might be the primary event in the genesis of some intestinal tumours (Chawengsaksophak et. al., 2004; Chawengsaksophak et. al., 1997).]


Beck, F., Erler, T., Russell, A., and James, R. (1995). Expression of Cdx-2 in the mouse embryo and placenta: possible role in patterning of the extra-embryonic membranes. Dev Dyn 204, 219-227.

Chawengsaksophak, K., de Graaff, W., Rossant, J., Deschamps, J., and Beck, F. (2004). Cdx2 is essential for axial elongation in mouse development. Proc Natl Acad Sci U S A 101, 7641-7645.

Chawengsaksophak, K., James, R., Hammond, V. E., Kontgen, F., and Beck, F. (1997). Homeosis and intestinal tumours in Cdx2 mutant mice. Nature 386, 84-87.

The three mouse cad homologues, Cdx1, Cdx2 and Cdx4, (2–4) have developmental roles with overlap of expression patterns.

Cdx2 is expressed (5) at 3.5 days postcoitum (dpc) in the trophectoderm but not in the inner cell mass. At 7.5 dpc (Theiler stage 11), it is present in the chorion, ectoplacental cone, mesoderm of the developing allantoic bud, and posterior primitive streak. At 8.5 dpc (Theiler stage 13), expression is seen in all three germ layers at the posterior end of the embryo extending into the mesodermal root of the allantois, in the endodermal epithelium of the hindgut rudiment, and in the neural tube; the presegmented paraxial mesoderm expresses the gene, but the somites, lateral plate, and intermediate mesoderm do not. By 9.5 dpc (Theiler stage 15), the caudal pole of the embryo remains positive, as does the posterior neural tube and posterior gut endoderm. At 12.5 dpc (Theiler stage 20), expression is confined exclusively to the gut endoderm posterior to the foregut midgut junction (5). [...]

Cdx1 expression extends most anteriorly, followed by Cdx2 and Cdx4, respectively, with all three genes expressed posteriorly. Cdx2-null mutant embryos die between 3.5 and 5.5 dpc, and heterozygotes have tail abnormalities and exhibit anterior homeotic shifts involving the cervical and upper thoracic vertebrae, ribs, and midgut endoderm (7).


5. Beck, F., Erler, T., Russell, A. & James, R. (1995) Dev. Dyn. 204, 219–227.

7. Chawengsaksophak, K., James, R., Hammond, V. E., Kontgen, F. & Beck, F. (1997) Nature 386, 84–87.

Anmerkungen

The source is given two times, but it is not clear that Chawengsaksophak et al. are quoted literally here. Also the reader rather assumes that the given source is just one more reference.

Sichter
(SleepyHollow02) Schumann

[17.] Vpr/Fragment 015 03 - Diskussion
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CDX2 is normally expressed in the gut during development and adulthood. However, its expression is lost in colorectal tumors and corresponding carcinoma cell lines (Ee et. al., 1995; Hinoi et. al., 2003; Hinoi et. al., 2001). A role for the loss of Cdx2 expression in colorectal carcinoma development can be inferred from the frequent occurrence of adenomatous intestinal polyps in Cdx2 heterozygous mutant mice.

Ee, H. C., Erler, T., Bhathal, P. S., Young, G. P., and James, R. J. (1995). Cdx-2 homeodomain protein expression in human and rat colorectal adenoma and carcinoma. Am J Pathol 147, 586-592.

Hinoi, T., Loda, M., and Fearon, E. R. (2003). Silencing of CDX2 expression in colon cancer via a dominant repression pathway. J Biol Chem 278, 44608-44616.

Hinoi, T., Tani, M., Lucas, P. C., Caca, K., Dunn, R. L., Macri, E., Loda, M., Appelman, H. D., Cho, K. R., and Fearon, E. R. (2001). Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon. Am J Pathol 159, 2239-2248.

CDX2 is normally expressed in the gut during development and adulthood52–54; however, its expression is lost in colorectal tumours and corresponding carcinoma cell lines32,55,56.A functional role for the loss of function of Cdx2 in colorectal carcinoma has been indicated by the frequent occurrence of ADENOMATOUS INTESTINAL POLYPS in Cdx2 heterozygous mutant mice57;

32. Ee, H. C., Erler, T., Bhathal, P. S., Young, G. P. & James, R. J. Cdx-2 homeodomain protein expression in human and rat colorectal adenoma and carcinoma. Am. J. Pathol. 147, 586–592 (1995).

52. James, R. & Kazenwadel, J. Homeobox gene expression in the intestinal epithelium of adult mice. J. Biol. Chem. 266, 3246–3251 (1991).

53. James, R., Erler, T. & Kazenwadel, J. Structure of the murine homeobox gene cdx-2. Expression in embryonic and adult intestinal epithelium. J. Biol. Chem. 269, 15229–15237 (1994).

54. Silberg, D. G., Swain, G. P., Suh, E. R. & Traber, P. G. Cdx1 and cdx2 expression during intestinal development. Gastroenterology 119, 961–971 (2000).

55. Mallo, G. V. et al. Molecular cloning, sequencing and expression of the mRNA encoding human Cdx1 and Cdx2 homeobox. Down-regulation of Cdx1 and Cdx2 mRNA expression during colorectal carcinogenesis. Int. J. Cancer 74, 35–44 (1997).

56. Hinoi, T. et al. Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon. Am. J. Pathol. 159, 2239–2248 (2001).

57. Chawengsaksophak, K., James, R., Hammond, V. E., Kontgen, F. & Beck, F. Homeosis and intestinal tumours in Cdx2 mutant mice. Nature 386, 84–87 (1997). [...]

Anmerkungen

The source is not mentioned here.

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(Hindemith) Schumann

[18.] Vpr/Fragment 015 26 - Diskussion
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1.5 Chromosomal Translocations

Recurring chromosomal abnormalities have been identified in a variety of cancers, but are most frequently associated with leukemias, lymphomas and sarcomas (Rabbitts, 1994; Rowley, 1999). At present, more than 500 recurring [cytogenetic abnormalities have been reported in hematological malignancies.]


Rabbitts, T. H. (1994). Chromosomal translocations in human cancer. Nature 372, 143-149.

Rowley, J. D. (1999). The role of chromosome translocations in leukemogenesis. Semin Hematol 36, 59-72.

4.2. Chromosomal translocations

Recurring chromosomal abnormalities have been identified in a variety of cancers, but are most frequently associated with leukemias, lymphomas and sarcomas (Rabbitts, 1994; Rowley, 1999). At present, more than 500 recurring cytogenetic abnormalities have been reported in hematological malignancies.


Rabbttis T. H. (1994). Chromosomal translocations in human cancer. Nature. 372 (6502), 143-9.

Rowley J. D. (1999). The role of chromosome translocations in leukemogenesis. Semin Hematol. 4 (7), 59-72.

Anmerkungen

Text is identical, the source is not mentioned.

The copied text is continued on the next page: Vpr/Fragment_016_01

Sichter
(Hindemith) Schumann

[19.] Vpr/Fragment 016 01 - Diskussion
Bearbeitet: 17. March 2014, 12:29 Graf Isolan
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[At present, more than 500 recurring] cytogenetic abnormalities have been reported in hematological malignancies. Three main cytogenetic changes have been detected in hematological malignancies: deletions, inversions and translocations. At present, more than 500 recurring cytogenetic abnormalities have been reported in hematological malignancies. Three main cytogenetic changes have been detected in hematological malignancies: deletions, inversions and translocations.
Anmerkungen

The text is identical, the source is not mentioned.

The copied text starts on the previous page: Vpr/Fragment_015_26.

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(Hindemith) Schumann

[20.] Vpr/Fragment 016 17 - Diskussion
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There are at least seven different chromosomal translocations associated with a myeloproliferative disease. These include the BCR/ABL, ETV6/ABL, ETV6/PDGFRB, HIP1/PDGFRB, H4/PDGFRB, RAB5E/PDGFRB, and ETV6/JAK2 fusions (table 1) (Dash and Gilliland, 2001).

Table 1: Translocations involving tyrosine kinases

MPD = myeloproliferative disease

16a diss Vpr.png


Dash, A., Gilliland, D. G. (2001) Molecular genetics of acute myeloid leukaemia. Best Pract Res Clin Haematol 14, 49-64.

There are at least seven different chromosomal translocations associated with myeloproliferative disease. These include the BCR/ABL, ETV6/ABL, ETV6/PDGFRB, HIP1/PDGFRB, H4/PDGFRB, RAB5E/PDGFRB, and ETV6/JAK2 fusions (Table 4.1 adapted from Dash, 2001).

Table 4.1: Chromosomal translocations involving tyrosine kinases

16a source Vpr.png

MPD = myeloproliferative disease


Dash A., Gilliland D. G. (2001). Molecular genetics pf [sic] acute myeloid leukaemia. Best Pract Res Clin Haematol. 14, 49-64.

Anmerkungen

The source is not given.

Note that in Dash & Gilliland (2001) the table and the text cannot be found in this form.

Sichter
(Hindemith) Schumann

[21.] Vpr/Fragment 019 01 - Diskussion
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The failure of certain fusion genes to induce leukemia on their own in animal models as well as the fact that more than 50% of acute myeloid leukemias do not have apparent cytogenetic abnormalities, point to the role of point mutations in or, alternatively, the aberrant expression of proto-oncogenes in the development of leukemia. These observations also suggest that the aberrant expression of proto-oncogenes might be more common than is generally believed. The sheer number of ETV6 fusions in AML allows for the study of a diverse group of leukemias in which more than one of the aforementioned mechanisms might be operating. The t(12;13) translocation is particularly interesting in this regard as the expression of both the ETV6/CDX2 fusion gene as well as the ectopic expression of the CDX2 gene has been demonstrated.

1.6 ETV6

ETV6 (ETS variant gene 6) was originally called TEL, for translocation ets leukemia gene. ETV6 is a member of the ets (E-26 transforming specific) family of transcription factors. All ets family proteins share a conserved protein domain of about 88 amino acids in length, the so called ets domain (see Figure 10) (Bohlander SK 2005). The ets domain is a sequence specific DNA binding domain but it also mediates protein-protein interaction. The other evolutionarily conserved domain is the N terminally located pointed or SAM (sterile alpha motif) domain in the 652 amino acids of ETV6 (Bohlander SK 2005). This domain is also called HLH (helix loop helix) domain. It is found in yeast proteins and has been shown to be involved in homo and heterodimerization of transcription factors and in signal transducing proteins (e.g. of the MAPK pathway) (Fig.10). ETV6 contains two alternative translational start codons (position 1 and position 43), leading to the expression of two isoforms of ETV6.


Bohlander S K (2005). ETV6: a versatile player in leukemogenesis.Semin Cancer Biol 15(3):162-74.

The failure of certain fusion genes to induce leukemia on their own, in animal models, as well as the fact that more than 50% of acute myeloid leukemias do not have apparent cytogenetic abnormalities, point to the role of point mutations in or, alternatively, the aberrant expression of proto-oncogenes in the development of leukemia. These observations also suggest that the aberrant expression of proto-oncogenes might be more common than is generally believed.

The sheer number of ETV6 fusions in AML allows for the study of a diverse group of leukemias in which more than one of the aforementioned mechanisms might be operating. The t(6;12) translocation is one of several that involve ETV6, in this case ETV6 is fused to STL gene in a B-cell ALL cell line.

4.3. ETV6

ETV6 is a member of the ets (E-26 transforming specific) family of transcription factors. All ets family proteins share a highly conserved protein domain of about 88 amino acids in length the so-called ets domain. The ets domain is a sequence specific DNA binding domain but is [sic] also mediates protein-protein interaction (Figure 4.7, modified from Slupsky, 1998), it is

[page 21]

evolutionarily highly conserved and found in invertebrates such as Drosophila and C. elegans (Oikawa, 2003; Wasylyk, 1993).

The other evolutionarily conserved domain in the 652 amino acids of ETV6 is the N-terminally located pointed or sterile alpha motif (SAM) domain (Figure 4.7). This domain is also called HLH domain and is even more highly conserved in evolution and found in many ets family member. It is found in yeast proteins and has been shown to be involved in homo and heterodimerization in transcription factors and in signal transducing proteins (e.g. of the MAPK pathway) (Grimshaw, 2004). ETV6 contains two alternative translational start codons (position 1 and position 43) leading to the expression of two isoforms of ETV6.

Anmerkungen

The source is not given.

Note that the text of the second part of the fragment can also be found in Bohlander (2005), see Vpr/Dublette/Fragment 019 13. However, despite the fact that Vpr mentions Bohlander (2005) in the text, the likely source is still the here documented Fontanari Krause (2006), because the text there is closer to Bohlander (2005), in particular containing text fragments not included in Vpr (e.g. the half-sentence: "and is even more highly conserved in evolution and found in many ets family member"), such that it is not likely that Fontanari Krause (2006) copied from Vpr, more likely is the other way round. It is also unlikely that both authors copied from Bohlander (2005) independently as there are passages in close proximity that can be found in Vpr and in Fontanari Krause (2006) but not in Bohlander (2005)

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(SleepyHollow02), (Hindemith), Schumann

[22.] Vpr/Fragment 020 01 - Diskussion
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20a diss Vpr.png

Figure 10. ETV6 protein structure.

1.6.1 Role of ETV6 in hematopoiesis

ETV6 is widely expressed throughout embryonic development and in the adult. Embryos with a conventional knockout (KO) of the Etv6 gene die by day 11 of embryonic development (E11) due to vascular abnormalities. Blood formation in the embryo is largely unperturbed (Wang et. al., 1997). Yet, studies using chimeric mice from Etv6-deficient embryonic stem (ES) cells suggested a requirement of Etv6 in bone marrow hematopoiesis. Inducible and lineagespecific gene disruption of Etv6 in adult hematopoiesis in mice suggests that it plays two important roles in hematopoietic differentiation. First, Etv6 controls the survival of HSCs so that its disruption indirectly affects the majority of all hematopoietic cells which have limited clonal life spans and eventually will extinguish without constant regeneration from HSCs. Secondly, Etv6 is required late in the development of the megakaryocyte lineage, where it presumably acts in concert with transcriptional regulators previously implicated in megakaryopoiesis (Hock et. al., 2004).

1.6.2 ETV6 fusion partners

Translocations involving the ETV6 gene contribute to leukemogenesis through at least 3 different mechanisms. One mechanism is the activation of kinases. The second mechanism is the loss of function of critical transcription factors and/or the formation of aberrant transcription factors and the third mechanism is the induction of ectopic and aberrant expression of the proto-oncogene by the [chromosomal translocation.]


Hock, H., Meade, E., Medeiros, S., Schindler, J. W., Valk, P. J., Fujiwara, Y., and Orkin, S. H. (2004). Tel/Etv6 is an essential and selective regulator of adult hematopoietic stem cell survival. Genes Dev.

Wang, L. C., Kuo, F., Fujiwara, Y., Gilliland, D. G., Golub, T. R., and Orkin, S. H. (1997). Yolk sac angiogenic defect and intra-embryonic apoptosis in mice lacking the Ets-related factor TEL. Embo J 16, 4374-4383.

[page 21]

20a source Vpr.png

Figure 4.7: ETV6 protein structure. The pointed domain is represented between Nt 38 and Nt 123; ETS domain is between Nt 338 and Nt 422 (modified from Slupsky, 1998).

4.3.1. Role of ETV6 in hematopoiesis

ETV6 is widely expressed throughout embryonic development and in the adult. Embryos with a conventional knockout (KO) of the Etv6 gene die by day 11 of embryonic development (E11) due to vascular abnormalities. Blood formation in the embryo is largely unperturbed (Wang, 1997). Yet, studies using chimeric mice from Etv6-deficient embryonic stem (ES) cells suggested a requirement of Etv6 in bone marrow hematopoiesis. Inducible and lineagespecific gene disruption of Etv6 in adult hematopoiesis in mice suggests that it plays two important roles in hematopoietic differentiation. First, Etv6 controls the survival of HSCs so that its disruption indirectly affects the majority of all hematopoietic cells which have limited clonal life spans and eventually will extinguish without constant regeneration from HSCs.

[page 22]

Secondly, Etv6 is required late in the development of the megakaryocyte lineage, where it presumably acts in concert with transcriptional regulators previously implicated in megakaryopoiesis (Hock, 2004).

4.3.2. ETV6 fusion partners

Translocations involving the ETV6 gene contribute to leukemogenesis through at least 3 different mechanisms. One mechanism is the activation of kinases. The second mechanism is the loss of function of critical transcription factors and/or the formation of aberrant transcription factors and the third mechanism is the induction of ectopic and aberrant expression of the proto-oncogene by the chromosomal translocation.


Hock H., Meade E., Medeiros S., Schindler J. W., Valk P. J., Fujiwara Y., Orkin S. H. (2004). Tel/Etv6 is an essential and selective regulator of adult hematopoietic stem cell survival. Genes Dev. 18 (19), 2336-41.

Wang L. C., Kuo F., Fujiwara Y., Gilliland D. G., Golub T. R., Orkin S. H. (1997). Yolk sac angiogenic defect and intra-embryonic apoptosis in mice lacking the Ets-related factor TEL. EMBO J. 16, 4374-83.

Anmerkungen

The source is not mentioned. For the figure neither the original source Slupsky (1998) is mentioned.

Note that much of section 1.6.1 can also be found verbatim in Hock et al. (2004). This includes the reference to Wang (1997).

Sichter
(SleepyHollow02) Schumann, Hindemith

[23.] Vpr/Fragment 021 03 - Diskussion
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21a diss Vpr.png

Figure 11. This is a schematic diagram representing the various breakpoints of ETV6 (indicated by arrows) in the translocations involving different partner genes (indicated in closed boxes)

21b source Vpr.png

Figure 4.8: Diagram of ETV6 with protein domain and breakpoints (indicated by arrows) representing different partner genes of ETV6 (indicated in closed boxes) (adapted from Bohlander, 2005).

Anmerkungen

The image is copied from the source without this being made clear.

Note that the same figure can also be found in the original source Quelle:Vpr/Bohlander_2005, see Vpr/Dublette/Fragment_021_03. Inspecting the figure caption one can see that the caption of Fontanari Krause (2006) lies somewhat in between the versions of Vpr and Quelle:Vpr/Bohlander_2005, which suggests that Vpr adapted it from Fontanari Krause (2006) who adapted it from Quelle:Vpr/Bohlander_2005.

The next figure (Figure 12) that also comes from the source is marked with: "(kindly provided by Prof. Stefan Bohlander)".

Sichter
(Hindemith) Schumann

[24.] Vpr/Fragment 021 10 - Diskussion
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1.6.3 Protein tyrosine kinase fusion partners of ETV6

The first identified fusion partner of ETV6 was a protein tyrosine kinase (PTK), the platelet-derived growth factors receptor beta (PDGFRB) (Golub et. al., 1994). The fusion protein critical for the development of the chronic myelo-[monocytic leukemia is the ETV6/PDGFRB fusion and not the reciprocal PDGFRB/ETV6 fusion.]


Golub, T. R., Barker, G. F., Lovett, M., and Gilliland, D. G. (1994). Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 77, 307-316.

4.3.3. Protein tyrosine kinase fusion partners of ETV6

The first identified fusion partner of ETV6 was a protein tyrosine kinase (PTK), the platelet-derived growth factors receptor beta (PDGFRB) (Golub, 1994a). The fusion protein critical for the development of the chronic myelomonocytic leukemia is the ETV6/PDGFRB fusion, and not the reciprocal PDGFRB/ETV6 fusion.


Golub, T. R., Barker G.F., Lovett M., Gilliland D. G. (1994a). Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell. 77 (2), 307-16.

Anmerkungen

The source is not mentioned here.

The copied text continues on the next page Vpr/Fragment_022_01.

Note that the text is also quite similar to another source, see: Vpr/Dublette/Fragment_021_10

Sichter
(Hindemith) Schumann

[25.] Vpr/Fragment 022 01 - Diskussion
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[The fusion protein critical for the development of the chronic myelo-]monocytic leukemia is the ETV6/PDGFRB fusion and not the reciprocal PDGFRB/ETV6 fusion. In the ETV6/PDGFRB fusion protein the N terminal portion of ETV6, which includes the pointed domain, is fused to the C-terminal two thirds of the PDGFRB protein, conserving the tyrosine kinase domain of PDGFRB. The fusion of the pointed domain of ETV6 in the N-terminal half with the tyrosine kinase domain in the C-terminal half of the fusion partner is characteristic of the class of ETV6/PTK fusions and is found in the fusions of ETV6 with ABL1, ABL2, JAK2, NTRK3, FGFR3 and SYK (Fig. 11) (Table 2) (Papadopoulos et. al., 1995; Cazzaniga et. al., 1999; Knezevich et. al., 1998; Kuno et. al., 2001; Peeters et. al., 1997)

Table2. Tyrosine kinase fusion partners of ETV6

22a diss Vpr.png

1.6.4 Transcription factors and other fusion partners of ETV6

The ETV6/RUNX1 (ETV6/AML1) fusion is the most common fusion gene in childhood acute B cell lymphoblastic leukemia (Shurtleff et. al., 1995).


Cazzaniga, G., Tosi, S., Aloisi, A., Giudici, G., Daniotti, M., Pioltelli, P., Kearney, L., and Biondi, A. (1999). The tyrosine kinase abl-related gene ARG is fused to ETV6 in an AML-M4Eo patient with a t(1;12)(q25;p13): molecular cloning of both reciprocal transcripts. Blood 94, 4370- 4373.

Knezevich, S. R., McFadden, D. E., Tao, W., Lim, J. F., and Sorensen, P. H. (1998). A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet 18, 184-187.

Kuno, Y., Abe, A., Emi, N., Iida, M., Yokozawa, T., Towatari, M., Tanimoto, M., and Saito, H. (2001). Constitutive kinase activation of the TEL-Syk fusion gene in myelodysplastic syndrome with t(9;12)(q22;p12). Blood 97, 1050-1055.

Papadopoulos, P., Ridge, S. A., Boucher, C. A., Stocking, C., and Wiedemann, L. M. (1995). The novel activation of ABL by fusion to an ets-related gene, TEL. Cancer Res 55, 34-38.

Peeters, P., Raynaud, S. D., Cools, J., Wlodarska, I., Grosgeorge, J., Philip, P., Monpoux, F., Van Rompaey, L., Baens, M., Van den Berghe, H., and Marynen, P. (1997a). Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. Blood 90, 2535- 2540.

Peeters, P., Wlodarska, I., Baens, M., Criel, A., Selleslag, D., Hagemeijer, A., Van den Berghe, H., and Marynen, P. (1997b). Fusion of ETV6 to MDS1/EVI1 as a result of t(3;12)(q26;p13) in myeloproliferative disorders. Cancer Res 57, 564-569.

Shurtleff, S. A., Buijs, A., Behm, F. G., Rubnitz, J. E., Raimondi, S. C., Hancock, M. L., Chan, G. C., Pui, C. H., Grosveld, G., and Downing, J. R. (1995). TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis. Leukemia 9, 1985-1989.

The fusion protein critical for the development of the chronic myelomonocytic leukemia is the ETV6/PDGFRB fusion, and not the reciprocal PDGFRB/ETV6 fusion. In the ETV6/PDGFRB fusion protein the N terminal portion of ETV6, which includes the pointed domain, is fused to the C-terminal two thirds of the PDGFRB protein, conserving the tyrosine kinase domain of PDGFRB. The fusion of the pointed domain of ETV6 in the N-terminal half with the tyrosine kinase domain in the C-terminal half of the fusion partner is characteristic of the class of ETV6/PTK fusions

[page 23]

and is found in the fusions of ETV6 with ABL1, ABL2, JAK2, NTRK3, FGFR3 and SYK (Table 4.2 adapted from Bohlander, 2005) (Papadopoulos, 1995; Cazzaniga, 1999; Kuno, 2001).

Table 4.2: Protein tyrosine kinase fusion partner of ETV6

22b source Vpr.png

4.3.4. Transcription factors and other fusion partners of ETV6

The ETV6/RUNX1 (ETV6/AML1) fusion is the most common fusion gene in childhood acute B cell lymphoblastic leukemia (Shurtleff, 1995).


Bohlander S. K. (2005). ETV6: A versatile player in leukemogenesis. Semin Cancer Biol. 15 (3), 162-74.

Cazzaniga G., Tosi S., Aloisi A., et al. (1999). The tyrosine kinase abl-related gene ARG is fused to EYV6 in an AML-M4Eo patient with a t(1;12)(q25;p13): molecular cloning of both reciprocal transcripts. Blood. 94, 4370-73.

Kuno Y., Abe a., Emi N., Iida M., Yokozawa t., towatari M., et al. (2001). Constitutive kinase activation of the TEL-Syk fusion gene in myelodysplastic syndrome with t(9;12)(q22;p12). Blood. 97, 1050-5.

Papadopoulos P., Rigde S. A., Boucher C. A., Stocking C., Wiedemann L. M. (1995). The novel activation of ABL by fusion to an ets-related gene, TEL. Cancer Res. 55 (1), 34-8.

Shurtleff S. A., Buijs A., Behm F. G., Rubnitz J. E., Raimondi S. C., Hancock M. L., Chan G. C., Pui C. H., Grosveld G., Downing J. R. (1995).TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent. Leukemia. 9 (12), 1985-9.

Anmerkungen

The source is not mentioned here.

Note that the table in the source Fontanari Krause (2006) has the same columns as Vpr but a different order of the columns. The original source Bohlander (2005) has the same column order as Fontanari Krause (2006), but two additional columns that appear neither in Vpr nor in Fontanari Krause (2006). This can be interpreted as indication that Vpr copied from Fontanari Krause (2006) who copied from Bohlander (2005).

Note that there are two publicationen "Peeters et. al., 1997" in the bibliography.

Note also that Vpr is closer to Fontanari Krause (2006) than to Bohlander (2005), see Vpr/Dublette/Fragment_022_01. However, Vpr includes two references: Knezevich et al. (1998) and Peeters et al. (1997) that also Bohlander (2005) mentions, but Fontanari Krause (2006) does not.

Sichter
(Hindemith) Schumann

[26.] Vpr/Fragment 023 01 - Diskussion
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[1.6.4 Transcription factors and other fusion partners of ETV6

The ETV6/RUNX1 (ETV6/AML1) fusion is the most common fusion gene in childhood acute B cell lymphoblastic leukemia (Shurtleff et. al., 1995). Re-]porter gene assays showed that the ETV6/RUNX1 fusion protein acts as a repressor by binding to the promoter and enhancer regions of RUNX1 target genes. This repression function is dependent on the pointed and on the central domain of ETV6, which are both part of the ETV6 portion of the ETV6/RUNX1 fusion protein (Fenrick et. al., 1999). ETV6/ARNT and HLXB9/ETV6 chimeric proteins are other examples of this class of ETV6 fusions found in AML and the HLXB9/ETV6 hybrid is detected in up to 20% of pediatric cases with AML (Beverloo et al., 2001) A potential mechanism of transformation for these fusions is that the ETV6/ARNT and HLXB9/ETV6 proteins interact with the wild-type ETV6 through the pointed domain, thereby interfering with normal ETV6 function (Beverloo et. al., 2001).

1.6.5 Ectopic and aberrant expression of a proto-oncogene gene

A number of ETV6 translocations including the ETV6-MDS1/EVI1 and the ETV6-CDX2 fusion only contain the transcription/translation start of ETV6 (Peeters et al., 1997, Chase et al., 1999). In these cases ectopic expression of the transcription factors EVII and CDX2 was detected in addition to the expression of the fusion gene. The potential importance of the ectopic expression of a proto-oncogene in this class of ETV6 fusions was further underlined by observations that the ectopic expression of the proto-oncogene also occurred when the fusion gene itself was not translated into a protein product. For example patients with the t(4;12) positive leukemia show ectopic expression of the ParaHox gene GSH2. However the fusion gene CHIC2-ETV6 generated by the chromosomal translocation was not translated into a protein product. Furthermore, expression of IL-3 was observed in a CML case with a t(5;12), lacking the ETV6-ACS2 fusion protein. These results suggest that ectopic expression of GSH2 and IL-3 could be the key leukemogenic mechanism in these leukemias (Cools et. al., 2002).


Beverloo, H. B., Panagopoulos, I., Isaksson, M., van Wering, E., van Drunen, E., de Klein, A., Johansson, B., and Slater, R. (2001). Fusion of the homeobox gene HLXB9 and the ETV6 gene in infant acute myeloid leukemias with the t(7;12)(q36;p13). Cancer Res 61, 5374-5377.

Chase, A., Reiter, A., Burci, L., Cazzaniga, G., Biondi, A., Pickard, J., Roberts, I. A., Goldman, J. M., and Cross, N. C. (1999). Fusion of ETV6 to the caudal-related homeobox gene CDX2 in acute myeloid leukemia with the t(12;13)(p13;q12). Blood 93, 1025-1031.

Cools, J., Mentens, N., Odero, M. D., Peeters, P., Wlodarska, I., Delforge, M., Hagemeijer, A., and Marynen, P. (2002). Evidence for position effects as a variant ETV6-mediated leukemogenic mechanism in myeloid leukemias with a t(4;12)(q11-q12;p13) or t(5;12)(q31;p13). Blood 99, 1776- 1784.

Fenrick, R., Amann, J. M., Lutterbach, B., Wang, L., Westendorf, J. J., Downing, J. R., and Hiebert, S. W. (1999). Both TEL and AML-1 contribute repression domains to the t(12;21) fusion protein. Mol Cell Biol 19, 6566-6574.

Peeters, P., Raynaud, S. D., Cools, J., Wlodarska, I., Grosgeorge, J., Philip, P., Monpoux, F., Van Rompaey, L., Baens, M., Van den Berghe, H., and Marynen, P. (1997a). Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. Blood 90, 2535- 2540.

Peeters, P., Wlodarska, I., Baens, M., Criel, A., Selleslag, D., Hagemeijer, A., Van den Berghe, H., and Marynen, P. (1997b). Fusion of ETV6 to MDS1/EVI1 as a result of t(3;12)(q26;p13) in myeloproliferative disorders. Cancer Res 57, 564-569.

Shurtleff, S. A., Buijs, A., Behm, F. G., Rubnitz, J. E., Raimondi, S. C., Hancock, M. L., Chan, G. C., Pui, C. H., Grosveld, G., and Downing, J. R. (1995). TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis. Leukemia 9, 1985-1989.

[page 23]

4.3.4. Transcription factors and other fusion partners of ETV6

The ETV6/RUNX1 (ETV6/AML1) fusion is the most common fusion gene in childhood acute B cell lymphoblastic leukemia (Shurtleff, 1995). Reporter gene assays showed that the ETV6/RUNX1 fusion protein acts as a repressor by binding to the promoter and enhancer regions of RUNX1 target genes. This repression function is dependent on the pointed and on the central domain of ETV6, which are both part of the ETV6 portion of the ETV6/RUNX1 fusion protein (Fenrick, 1999). ETV6/ARNT and HLXB9/ETV6 chimeric proteins are other examples of this class of ETV6 fusions found in AML and the HLXB9/ETV6 hybrid is detected in up to 20% of pediatric cases with AML (Beverloo, 2001). A potential mechanism of transformation for these fusions is that the ETV6/ARNT and HLXB9/ETV6 proteins interact with the wild-type ETV6 through the pointed domain, thereby interfering with normal ETV6 function (Beverloo, 2001).

4.3.5. Ectopic and aberrant expression of a proto-oncogene gene

A number of ETV6 translocations including the ETV6-MDS1/EVI1 and the ETV6-CDX2 fusion only contain the transcription/translation start of ETV6 (Peeters, 1997; Chase, 1999). In these cases ectopic expression of the transcription factors EVI1 and CDX2 was detected in addition to the expression of the fusion gene.

[page 24]

The potential importance of the ectopic expression of a proto-oncogene in this class of ETV6 fusions was further underlined by observations that the ectopic expression of the proto-oncogene also occurred when the fusion gene itself was not translated into a protein product: an example for this is the ectopic expression of the ParaHox gene GSH2 in patients with t(4;12) positive leukemia, even in cases, in which no protein expression of the CHIC2-ETV6 fusion generated by the chromosomal translocation, could be detected. Furthermore, expression of IL-3 was observed in a CML case with a t(5;12), lacking the ETV6-ACS2 fusion protein. These results suggest that ectopic expression of GSH2 and IL-3 could be the key leukemogenic mechanism in these leukemias (Cools, 2002).


Beverloo H. B., Panagopoulos I., Isaksson M., et al. (2001). Fusion of the homeobox gene HLXB9 and the ETV6 gene in infant acute myeloid leukemias with the t(7;12)(q36;p13). Cancer Res. 61, 5374-77.

Chase A., Reiter A., Burci L., et al. (1999). Fusion of ETV6 to the caudal-related homeobox gene CDX2 in acute myeloid leukemia with the t(12;13)(p12;q12). Blood. 93, 1025-31.

Cools J., Mentens N., Odero M. D., et al. (2002). Evidence for position effects as a variant ETV6- mediated leukemogenic mechanism in myeloid leukemias with a t(4;12)(q11-q12;p13) or t(5;12)(q31;p13). Blood. 99, 1776-84.

Fenrick R., Amann J. M., Lutterbach B., et al. (1999). Both TEL and AML-1 contribute repression domains to the t(12;21) fusion protein. Mol Cell biol. 19, 6566-74.

Peeters P., Raynaud S. D., Cools J., et al. (1997). Fusion of TEL. the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a mueloid leukemia. Blood. 90, 2535-40.

Shurtleff S. A., Buijs A., Behm F. G., Rubnitz J. E., Raimondi S. C., Hancock M. L., Chan G. C., Pui C. H., Grosveld G., Downing J. R. (1995).TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent. Leukemia. 9 (12), 1985-9.

Anmerkungen

The source is not mentioned.

Note that the first two sentences can also be found in Bohlander (2005), but Fontanari Krause (2006) is the more likely source.

Note that there are two references "Peeters et al., 1997" in the bibliography.

Sichter
(SleepyHollow02) Schumann, Hindemith

[27.] Vpr/Fragment 024 03 - Diskussion
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The t(12;13)(p13;q12) translocation was discovered by Chase and coworkers in 1999 in a rare case of AML and was shown to result in the novel fusion between ETV6 and caudal related homeobox gene CDX2 (Chase et. al., 1999). Interestingly, it was noted at that time that a non-rearranged CDX2 mRNA was expressed at high levels in this patient. Normally, CDX2 is not expressed in adult hematopoiesis.

Chase, A., Reiter, A., Burci, L., Cazzaniga, G., Biondi, A., Pickard, J., Roberts, I. A., Goldman, J. M., and Cross, N. C. (1999). Fusion of ETV6 to the caudal-related homeobox gene CDX2 in acute myeloid leukemia with the t(12;13)(p13;q12). Blood 93, 1025-1031.

The t(12;13)(p13;q12) translocation found in rare cases of AML was shown to result in one case in the fusion of ETV6 with the caudal related homeobox gene CDX2 [69]. The breakpoint in this case was after exon 2 of ETV6. Interestingly, it was noted at that time that a non-rearranged CDX2 mRNA was expressed at high levels in this patient. Normally, CDX2 is only expressed in the epithelia of the gut and in early development.

[69] Chase A, Reiter A, Burci L, Cazzaniga G, Biondi A, Pickard J, et al. Fusion of ETV6 to the caudal-related homeobox gene CDX2 in acute myeloid leukemia with the t(12;13)(p13;q12). Blood 1999;93:1025–31.

Anmerkungen

The source is not given.

Sichter
(Hindemith) Schumann

[28.] Vpr/Fragment 030 13 - Diskussion
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For retroviral gene transfer into primary bone marrow (BM) cells, the different constructs were subcloned into the multiple cloning site of the modified MSCV 2.1 vector (Pineault et. al., 2003b) upstream of the internal ribosomal entry site (IRES) and the enhanced green or yellow fluorescent protein (GFP/YFP) gene. As a control the MSCV vector carrying only the IRESEGFP cassette was used.

Pineault, N., Buske, C., Feuring-Buske, M., Abramovich, C., Rosten, P., Hogge, D. E., Aplan, P. D., and Humphries, R. K. (2003). Induction of acute myeloid leukemia in mice by the human leukemia- specific fusion gene NUP98-HOXD13 in concert with Meis1. Blood 101, 4529-4538.

For retroviral gene transfer into primary bone marrow (BM) cells, the murine OSTL (clone J16) was subcloned into the multiple cloning site of the modified MSCV 2.1 vector (Pineault et al., 2003) upstream of the internal ribosomal entry site (IRES) and the enhanced green fluorescent protein (GFP) gene (2.2.7.1). As a control, the empty MSCV vector carrying was used.

Pineault N., Buske C., Feuring-Buske M., Abramovich C., Rosten P., Hogge D. E., Aplan P. D., Humphries R. K. (2003). Induction of acute myeloid leukemia in mice by the human leukemia-specific fusion gene NUP98-HOXD13 in concert with Meis1. Blood. 101 (11), 4529-38.

Anmerkungen

The source is not mentioned.

Note that there is no "Pineault et. al., 2003b" in the list of references.

Sichter
(Hindemith) Schumann

[29.] Vpr/Fragment 032 01 - Diskussion
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3.3 Retrovirus Production.

Retrovirus was produced with the constructs mentioned before by individually co-transfecting 15 μg of the construct DNA with equal amounts of Ecopac DNA into 293T cells by using the calcium chloride precipitation method of transfection (Pineault et. al., 2003b). Virus conditioned medium (VCM) was collected 48h after transfection at time intervals of eight hours for forty-eight hours. Production of high-titer helper-free retrovirus was achieved by transducing the ecotropic packaging cell line GP+E86 (Pineault et al., 2003b) with virus conditioned medium (VCM) from 293T transfected cells. Successfully transduced GP+E86 cells were sorted out by FACS using GFP or YFP as a marker 4 days after transduction using standard procedures (Pineault et. al., 2003a).


Pineault, N., Buske, C., Feuring-Buske, M., Abramovich, C., Rosten, P., Hogge, D. E., Aplan, P. D., and Humphries, R. K. (2003). Induction of acute myeloid leukemia in mice by the human leukemia- specific fusion gene NUP98-HOXD13 in concert with Meis1. Blood 101, 4529-4538.

[page 90]

5.10.2. Retrovirus Production

Retrovirus was produced with the constructs mentioned above by co-transfecting 30 μg of the construct plasmid DNA with equal amounts of Ecopac DNA into 293T cells using the

[page 91]

calcium phosphate precipitation method (Pineault et al., 2003). Virus conditioned medium (VCM) was collected 48h after transfection at time intervals of eight hours for forty-eight hours. Production of high-titer helper-free retrovirus was achieved by transducing the ecotropic packaging cell line GP+E86 (Pineault et al., 2003) with virus conditioned medium (VCM) from 293T transfected cells. Successfully transduced GP+E86 cells were sorted out by FACS using GFP as a marker 4 days after transduction using standard procedures (Pineault et al., 2003).


Pineault N., Buske C., Feuring-Buske M., Abramovich C., Rosten P., Hogge D. E., Aplan P. D., Humphries R. K. (2003). Induction of acute myeloid leukemia in mice by the human leukemiaspecific fusion gene NUP98-HOXD13 in concert with Meis1. Blood. 101 (11), 4529-38.

Anmerkungen

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Note that there is only one source "Pineault et al. (2003) listed in the bibliography.

Note that in Pineault et al. (2003) (the paper listed in the bibliography) the here documented parallel text cannot be found.

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3.4 Retroviral infection of primary BM cells.

Primary mouse bone marrow (BM) cells were transduced as previously described (Pineault et. al., 2003a). Briefly, BM cells were obtained by flushing both femurs and tibias of donor mice treated 4 days previously with 150 mg/kg 5-fluorouracil injected into the tail vein. 5-flourouracil eliminates cycling cells from the animal, thus enriching the bone marrow for primitive hematopoietic progenitors, which are non-cycling or quiescent in nature (Reya et. al., 2001). Cells were stimulated for 48 hrs in DMEM supplemented with 15% FBS, 10 ng/ml mIL-6, 6 ng/ml mIL-3 and 100 ng/ml murine stem cell factor (SCF). For transduction, cells were co-cultured for 48h with irradiated (40 Gy) GP+E86 virus producing cells in the same medium with an addition of 5 μg/ml protamine sulfate with ETV6/CDX2/GFP or Cdx2/YFP GP+E86 producers or with a mixture of 40 to 50% CDX2/YFP and 50 to 60% ETV6/CDX2/GFP producers in co-transduction experiments. Protamine sulfate prevents aggregation of viral particles, thus increasing efficiency of transduction. Loosely adherent and nonadherent BM cells were harvested from the co-culture 48h post transduction, BM cells were furtherer cultured in fresh medium with cytokine cocktail for 48h to allow expression of EGFP or EYFP. Transduced BM cells were sorted out by florescence activated cell sorting (FACS) using EGFP or EYFP as a marker.

In Vitro Assays

3.5 Proliferation Assay.

To study the proliferative potential in vitro of BM cells transduced with ETV6/CDX2, Cdx2, its mutants and ETV6/CDX2 + Cdx2, we performed a proliferation assay by plating an equal number of successfully transduced bone marrow cells directly after sorting in DMEM supplemented with 15% FBS, 10 ng/ml mIL-6, 6 ng/ml mIL-3 and 100 ng/ml mSCF (standard medium) (Tebubio GmbH, Offenbach, Germany) at 370C in a humidified CO2 incubator. The [cells were subjected to half-media change every 7 days and their proliferation assessed on the same day by counting viable cells after trypan exclusion.]

[page 91]

5.10.3. Retroviral infection of primary BM cells

Primary mouse bone marrow (BM) cells were transduced as previously described (Pineault et al., 2003). Briefly, BM cells were obtained by flushing both femurs and tibias of donor mice treated 4 days previously with 150 mg/kg 5-fluorouracil (myeloid condition) injected into the tail vein. Mice without 5-fluorouracil treatment (for lymphoid condition) were also used in this work. 5-flourouracil eliminates cycling cells hematopoietic cells from the animal, thus enriching the bone marrow for primitive hematopoietic progenitors, which are non-cycling or quiescent in nature (Reya, 2001). Cells were stimulated for 48 hrs in DMEM supplemented with 15% FBS, 10 ng/ml IL6, 6 ng/ml IL3 and 10 ng/ml mSCF.

For lymphoid condition assays, cells were stimulated for 24 h in DMEM supplemented with 15% FBS, 10 ng/ml IL7, 6 ng/ml mutant FLT3 and 10 ng/ml mSCF.

For transduction, cells were co-cultured for 48h with irradiated (40 Gy) GP+E86 virus producing cells in the same medium with the addition of 5 μg/ml protamine sulfate. Protamine sulfate prevents aggregation of viral particles, thus increasing efficiency of transduction. Loosely adherent and non-adherent BM cells were harvested from the coculture 48h post transduction, BM cells were furtherer cultured in fresh medium with cytokine cocktail for 48 h or 24 h (myeloid or lymphoid condition) to allow expression of EGFP. Transduced BM cells were sorted by fluorescence activated cell sorting (FACS) using EGFP as a marker.

5.10.4. In Vitro Assays

5.10.4.1. Proliferation Assay

To study the proliferative potential in vitro of BM cells transduced with OSTL expressing retroviruses, a proliferation assay was performed by plating successfully transduced bone marrow cells directly after sorting in DMEM supplemented with 15% FBS, 10 ng/ml mIL-

[page 92]

6, 6 ng/ml mIL-3 and 100 ng/ml murine stem cell factor (SCF) (standard medium) (Tebubio GmbH, Offenbach, Germany) at 37°C in a humidified 5% CO2 incubator. The cells were subjected to half-media change every 7 days and their proliferation assessed on the day of media change by counting viable cells after trypan exclusion.

Anmerkungen

The source is not mentioned here.

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[The] cells were subjected to half-media change every 7 days and their proliferation assessed on the same day by counting viable cells after trypan exclusion. To generate IL-3 dependent cell lines, successfully transduced bone marrow cells were cultured directly after sorting in DMEM, 15% FBS with mIL-3 alone (6ng/ml). A half-media change was done every 7 days.

3.6 Colony Forming Cells Assay (CFC-assay).

To check the differentiation and clonogenic potential of the BM cells expressing the various genes mentioned above, we performed a CFC assay by testing colony formation in methylcellulose. The CFC–assay was performed by culturing highly purified transduced cells (500 /dish) in 35mm-diameter Petri dishes directly after sorting in 1ml methylcellulose supplemented with cytokines (Methocult M3434), and incubated at 370C in humidified CO2 incubator. Colonies were counted microscopically on 7 to 9 days after plating according to standard criteria (Schwaller et. al., 1998). Re-plating capacity of clonogenic progenitors was assayed by re-plating the primary colonies on secondary methylcellulose dishes. Again colonies were counted day at 7 to 9 after the secondary re-plating.

The cells were subjected to half-media change every 7 days and their proliferation assessed on the day of media change by counting viable cells after trypan exclusion. To generate IL-3 dependent cell lines, successfully transduced bone marrow cells were cultured directly after sorting in DMEM, 15% FBS with IL-3 alone (6 ng/ml). A half-media change was done every 7 days.

5.10.4.2. Colony Forming Cells Assay (CFC-assay)

To analyze the differentiation and clonogenic potential of the transduced BM cells, we performed CFC assays by testing colony formation in methylcellulose. The CFC–assay was done by culture highly purified transduced cells (500/dish) in 35mm-diameter Petri dishes directly after sorting in 1ml methylcellulose supplemented with cytokines (Methocult M3434). Colonies were counted microscopically on 7 to 9 days after plating according to standard criteria (Schwaller, 1998). Re-plating capacity of clonogenic progenitors was assayed by replating the primary colonies (500 cells/dish) on secondary methylcellulose dishes. Again colonies were counted at 7 to 9 days after the secondary re-plating.

Anmerkungen

The source is not mentioned here.

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3.8 Cyto-Morphology.

Cyto-morphological analysis of bone marrow was done by transferring 5x104 to 1x105 bone marrow cells on glass slide by centrifugation at 500 rpm for 10 minute using a Shandon Cytospin2 centrifuge. Slides were stained with May- Grunwald’s eosine-methylene blue and Giemsa solution using the standard protocol supplied by Merck.

3.9 Immunophenotyping:

Cell differentiation was determined and lineage distribution was checked by immunophenotyping. 5x104 to 1x104 cells were rinsed with PBS and stained for 30 minutes on ice with an appropriate concentration of phycoerythrin (PE) conjugated antibody to Gr-1, Sca1, Ter-119, CD4, and allophycocyanin-conjugated antibody for lineage markers Mac-1, cKit, B220 or CD8. The cells were then washed with PBS and stained with propidium iodide, and viable cells were analyzed with the FACS Calibur system.

[page 92]

5.10.5. Cyto-Morphology

Cyto-morphological analysis of bone marrow cells was done by transferring 5x104 to 1x105 bone marrow cells on glass slide by centrifugation at 500 rpm for 10 minute using a Shandon Cytospin2 centrifuge. Slides were stained with May-Grunwald’s eosine-methylene blue and Giemsa solution using the standard protocol supplied by Merck.

5.10.6. Immunophenotyping

Cell differentiation was determined and lineage distribution was analyzed by immunophenotyping. 5x104 to 1x104 cells were rinsed with PBS and stained for 30 minutes on ice with an appropriate concentration of phycoerythrin (PE) conjugated antibody to Gr- 1, Sca-1, Ter-119, CD4, and allophycocyanin-conjugated antibody for lineage markers Mac-1, cKit, B220 or CD8 (all Pharmingen Heidelberg, Germany). The cells were then

[page 93]

washed with PBS and stained with propidium iodide, and viable cells were analyzed with the FACS Calibur system.

Anmerkungen

The source is not given.

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3.12 BM transplantation and assessment of mice.

For bone marrow transplantation procedures, 8–10 week old recipient F1 (B6C3) mice were irradiated with 850 cGy from a 137Cs [sic] γ-radiation source. FACS purified transduced BM cells or defined ratios of transduced and untransduced cells were injected into the tail vein of irradiated recipient mice. PB or BM cell progeny of transduced cells were tracked using GFP or YFP fluorescence (Feuring-Buske et al., 2002). Lineage distribution was determined by flow cytometric analysis as previously described (Pineault et. al., 2003): Phycoerythrin-( PE) labeled Gr-1, Sca1, Ter-119, CD4 and allophycocyanin (APC) labeled Mac1, c-Kit, B220, CD8 antibodies were used for analysis (all Pharmingen Heidelberg, Germany). For histological analyses, sections of selected organs were prepared and H&E stained at the Academic Pathology Laboratory, GSF, Munich, using standard protocols. The mice were under observation for early signs of leukemia. Aspiration of the blood and bone marrow was performed at 8 weeks and subsequently at four week intervals and assessed for engraftment of the mouse with transduced cells and progression of disease. [...] In the animal, the indications of initiation of disease were paleness of the feet, limited mobility or lethargy, short breaths or ruffled body hair. Moribund mice were sacrificed and analyzed as described.


Feuring-Buske, M., Frankel, A. E., Alexander, R. L., Gerhard, B., and Hogge, D. E. (2002). A diphtheria toxin-interleukin 3 fusion protein is cytotoxic to primitive acute myeloid leukemia progenitors but spares normal progenitors. Cancer Res 62, 1730-1736.

Pineault, N., Buske, C., Feuring-Buske, M., Abramovich, C., Rosten, P., Hogge, D. E., Aplan, P. D., and Humphries, R. K. (2003). Induction of acute myeloid leukemia in mice by the human leukemia- specific fusion gene NUP98-HOXD13 in concert with Meis1. Blood 101, 4529-4538.

Pineault, N., Helgason, C. D., Lawrence, H. J., and Humphries, R. K. (2002). Differential expression of Hox, Meis1, and Pbx1 genes in primitive cells throughout murine hematopoietic ontogeny. Exp Hematol 30, 49-57.

5.10.7. BM transplantation and assessment of mice

For the bone marrow transplantation procedures, 8–10 week old recipient F1 (B6C3) mice were irradiated with 850 cGy from a 137Cs γ-radiation source. FACS purified transduced BM cells or defined ratios of transduced and unpurified and untransduced cells were injected into the tail vein of irradiated recipient mice.

PB or BM cell progeny of transduced cells were tracked using GFP fluorescence (Feuring Buske, 2002). Lineage distribution was determined by flow cytometric analysis as previously described (Pineault et al., 2003).

For histological analyses, sections of selected organs were prepared and H&E stained at the Academic Pathology Laboratory, GSF, Munich, using standard protocols. The mice were under observation for early signs of leukemia. Aspiration of the blood and bone marrow was performed at 8 weeks and subsequently at four week intervals and assessed for engraftment of the mice with transduced cells and progression of disease. The early signs of disease (leukemia) development were paleness of the feet, limited mobility or lethargy, shortness of breaths or ruffled body hair. Moribund mice were sacrificed and analyzed as described.


Feuring-Buske M., Frankel A. E., Alexander R. L., Gerhard B., Hogge D. E. (2002). A diphtheria toxin-interleukin 3 fusion protein is cytotoxic to primitive acute myeloid leukemia progenitors but spares normal progenitors. Cancer Res. 62 (6), 1730-6.

Pineault N., Buske C., Feuring-Buske M., Abramovich C., Rosten P., Hogge D. E., Aplan P. D., Humphries R. K. (2003). Induction of acute myeloid leukemia in mice by the human leukemiaspecific fusion gene NUP98-HOXD13 in concert with Meis1. Blood. 101 (11), 4529-38.

Anmerkungen

The source is not mentioned.

Note that there are two references "Pineault et. al., 2003" in the bibliography.

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(Hindemith) Schumann

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3.13 Analysis of sacrificed/dead experimental mice.

Disease in the animals was determined by analyzing PB, spleen and BM of diseased sacrificed mice. PB was aspirated from heart with 1 ml insulin syringes; Heparin was used for anticoagulation. PB was used for blood smears on glass slides and RBC count. WBC count and immunophenotyping was performed after lysing the RBC with ammonium chloride. The size of the spleen in diseased mice was measured and the spleen was homogenized to single cell suspension in DMEM medium, for further analysis by FACS, cytospin or ex vivo assays. BM cells were obtained by flushing both femurs and tibias and subjected to WBC count, cytospin and immunophenotyping.

3.14 Preparation for histopathology.

The four limbs, tail and head of mice were pinned to a cork plate with needles after sacrificing the animals for histological analyses. Then the skin from the chin to the anus and also the abdominal muscles were opened in the median and also pinned (Fig.16). The mice were then bled by cutting one of the renal arteries, and the blood was sucked out with a tissue paper. Then the diaphragm was carefully cut away to allow the fixing liquid to get into the thorax. After this the whole mouse was placed into formalin over night, packed and sent to the histopathology, where the organs were cut and stained for analyses (Fig.16).

[page 93]

5.10.8. Analysis of sacrificed/dead experimental mice

The PB, spleen and BM of sacrificed mice were analyzed carefully. PB was aspirated from heart with 1 ml insulin syringes; Heparin was used for anticoagulation. PB was used for blood smears on glass slides and RBC count. WBC count and immunophenotyping was performed after lysing the RBC with ammonium chloride. The spleen size was measured in diseased mice, and then homogenized for single cell suspension in DMEM medium, for further analysis by FACS, cytospin or ex vivo assays. BM cells were obtained by flushing both femurs and tibias and subjected to WBC count, cytospin and immunophenotyping.

[page 94]

5.10.9. Preparation for histopathology

The four limbs, tail and head of mice were pinned to a cork plate with needles after sacrificing the animals for histological analyses. Then the skin from the chin to the anus and also the abdominal muscles were opened in the median and also pinned down (Fig.2.3). The mice were then bled by cut one of the renal arteries, and the blood was sucked out with a tissue paper. Then the diaphragm was carefully cut away to allow the fixing liquid to penetrate into the thorax. After this the whole mouse was placed into formalin (37%) over night, packed and sent to the department of pathology (PD. Dr. Leticia Quintanilla-Fend), where the organs were cut and stained for analyses.

Anmerkungen

The source is not mentioned here.

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