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Typus
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SleepyHollow02
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Untersuchte Arbeit:
Seite: 23, Zeilen: 1-28
Quelle: Fontanari Krause 2006
Seite(n): 23, 24, Zeilen: 23: 6-20 - 24: 1-9
[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.

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(SleepyHollow02) Schumann, Hindemith

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