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Autor     Stefan K. Bohlander
Titel    ETV6: A versatile player in leukemogenesis
Zeitschrift    Seminars in Cancer Biology
Verlag    Elsevier
Ausgabe    15
Jahr    2005
Seiten    162–174
URL    http://www.sciencedirect.com/science/article/pii/S1044579X0500009X

Literaturverz.   

yes
Fußnoten    yes
Fragmente    5


Fragmente der Quelle:
[1.] Vpr/Dublette/Fragment 019 13 - Diskussion
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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. [...], which they called TEL (Translocation Ets Leukemia gene). TEL was later renamed to ETV6 (ets variant gene 6) by the nomenclature commission [...]

[...]

ETV6 is a member of the ets (E-26 transforming specific) family of transcription factors. All ets family proteins share a very conserved protein domain of about 88 amino acids in length the so-called ets domain (see Fig. 1). The ets domain is a sequence specific DNA binding domain but it also mediates protein-protein interaction, it is evolutionarily highly conserved and found in invertebrates such as Drosophila and C. elegans [4,5].

The other evolutionarily conserved domain in the 652 amino acids of ETV6 is the N-terminally located pointed or sterile alpha motif (SAM) domain whose 3D structure has recently been elucidated [6,7]. 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) [8]. ETV6 contains two alternative translationals start codons (position 1 and position 43) leading to the expression of two isoforms of ETV6.


[4] Oikawa T, Yamada T. Molecular biology of the Ets family of transcription factors. Gene 2003;303:11–34.

[5] Wasylyk B, Hahn SL, Giovane A. The Ets family of transcription factors. Eur J Biochem 1993;211:7–18.

[6] Tran HH, Kim CA, Faham S, Siddall MC, Bowie JU. Native interface of the SAM domain polymer of TEL. BMC Struct Biol 2002;2:5.

[7] Kim CA, Phillips ML, Kim W, Gingery M, Tran HH, Robinson MA, et al. Polymerization of the SAM domain of TEL in leukemogenesis and transcriptional repression. EMBO J 2001;20:4173–82.

[8] Grimshaw SJ, Mott HR, Stott KM, Nielson PR, Evetts KA, Hopkins LJ, et al. Structure of the sterile alpha motif (SAM) domain of the Saccharomyces cerevisiae mitogen-activated protein kinase pathway-modulating protein STE50 and analysis of its interaction with the STE11 SAM. J Biol Chem 2004;279:2192–201.

Anmerkungen

The source is mentioned twice, but it is not clear to the reader that the entire paragraph is taken from. In particular the passage after the second reference to the source is impossible to detect for the reader as a text of Bohrlander. Most likely, however, the immediate source has been different, see Vpr/Fragment_019_01

Note that the expression "the other evolutionarily conserved domain" is curious in the thesis, as there is no first "evolutionarily conserved domain". In the source there is a first one discussed, but this part was not copied.

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[2.] Vpr/Dublette/Fragment 021 03 - Diskussion
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21a diss Vpr

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)

21a source Vpr

Fig. 1. (A) Diagram of ETV6 with protein domains. The locations of the translocation breakpoints with the various fusion partners is noted

Anmerkungen

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

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

However, note that the likely source is Fontanari Krause (2006), see Vpr/Fragment_021_03

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[3.] Vpr/Dublette/Fragment 021 10 - Diskussion
Zuletzt bearbeitet: 2014-03-18 00:39:15 Hindemith
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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.

5. Protein tyrosine kinase fusion partners of ETV6

The first fusion partner of ETV6 was a protein tyrosine kinase (PTK), the platelet-derived growth factors receptor beta [3]. The fusion protein that is critical for the development of the chronic myelomonocytic leukemia and that has shown considerable transformation potential in cell line assays is the ETV6/PDGFRB fusion and not the reciprocal PDGFRB/ETV6 fusion.


[3] Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor ß to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 1994;77:307–16.

Anmerkungen

The source is not mentioned here.

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

Note that the most likely source is different, see: Vpr/Fragment_021_10

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[4.] Vpr/Dublette/Fragment 022 01 - Diskussion
Zuletzt bearbeitet: 2014-03-18 00:03:26 Hindemith
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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

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 that is critical for the development of the chronic myelomonocytic leukemia and that has shown considerable transformation potential in cell line assays 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, which includes the tyrosine kinase domain of PDGFRB. This general structure, i.e. pointed domain of ETV6 in the N-terminal half and tyrosine kinase domain in

[page 164]

the C-terminal half of the fusion protein, is characteristic of ETV6/PTK fusions and is found in the fusions of ETV6 to ABL1, ABL2, JAK2, NTRK3, FGFR3 and SYK (see Table 1 and Fig. 1) [11–18].

Table 1

Protein tyrosine kinase fusion partners of ETV6

22a source Vpr

[page 165]

6. Transcription factors and other fusion partners of ETV6

[...] Shortly after its discovery, the ETV6/RUNX1 fusion was recognized to be the most common fusion gene found in childhood acute B cell lymphoblastic leukemia [39].


[11] Papadopoulos P, Ridge SA, Boucher CA, Stocking C, Wiedemann LM. The novel activation of ABL by fusion to an ets-related gene, TEL. Cancer Res 1995;55:34–8.

[12] Cazzaniga G, Tosi S, Aloisi A, Giudici G, Daniotti M, Pioltelli P, et al. 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 1999;94:4370–3.

[13] Iijima Y, Ito T, Oikawa T, Eguchi M, Eguchi-Ishimae M, Kamada N, et al. A new ETV6/TEL partner gene, ARG (ABLrelated gene or ABL2), identified in an AML-M3 cell line with a t(1;12)(q25;p13) translocation. Blood 2000;95:2126–31.

[14] Lacronique V, Boureux A, Valle VD, Poirel H, Quang CT, Mauchauffe M, et al. A TEL–JAK2 fusion protein with constitutive kinase activity in human leukaemia. Science 1997;278:1309–12.

[15] Peeters P, Raynaud SD, Cools J, Wlodarska I, Grosgeorge J, Philip P, et al. 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 1997;90:2535–40.

[16] Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PH. A novel ETV6–NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet 1998;18:184–7.

[17] Yagasaki F, Wakao D, Yokoyama Y, Uchida Y, Murohashi I, Kayano H, et al. Fusion of ETV6 to fibroblast growth factor receptor 3 in peripheral T-cell lymphoma with a t(4;12)(p16;p13) chromosomal translocation. Cancer Res 2001;61:8371–4.

[18] Kuno Y, Abe A, Emi N, Iida M, Yokozawa T, Towatari M, et al. Constitutive kinase activation of the TEL–Syk fusion gene in myelodysplastic syndrome with t(9;12)(q22;p12). Blood 2001;97:1050–5.

[39] Shurtleff SA, Buijs A, Behm FG, Rubnitz JE, Raimondi SC, Hancock ML, et al. 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 1995;9:1985–9.

Anmerkungen

The source is not mentioned here.

Note that the table in the source has two more columns which have not been reproduced here in order to improve readability.

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

Note that also Fontanari Krause (2006) (p.22: 13ff) could have been the source of this text. In fact, this source is even closer to the text in the thesis, see Vpr/Fragment 022 01

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[5.] Vpr/Fragment 024 03 - Diskussion
Zuletzt bearbeitet: 2014-04-05 19:38:57 Hindemith
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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.

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