This proposal is based on the premise that after chromosomal rearrangements or other mutations disrupt its regulation, EVI1 is inappropriately expressed in CML cells and synergizes with the BCR/ABL pre-existing oncogene to give a highly proliferating and aggressive leukemic clone not responding to cytokines that control cellular growth or differentiation. By using a combination of molecular and biological assays, and by comparing the effects of EVI1 and MDS1/EVI1, it is proposed to identify the genes targeted by EVI1 and the mechanisms by which EVI1 inhibits IFNalpha-induced response. Finally, the applicant will begin a prospective study of CML patients to confirm that expression of EVI1 can be used as a prognostic marker for IFNalpha-therapy resistant patients. The ability to identify CML patients who will not respond to IFNalpha-therapy will be a very valuable clinical tool that could affect their treatment and their overall survival.
| Senyuk, Vitalyi; Premanand, Kavitha; Xu, Peng et al. (2011) The oncoprotein EVI1 and the DNA methyltransferase Dnmt3 co-operate in binding and de novo methylation of target DNA. PLoS One 6:e20793 |
| Dickstein, Jerome; Senyuk, Vitalyi; Premanand, Kavitha et al. (2010) Methylation and silencing of miRNA-124 by EVI1 and self-renewal exhaustion of hematopoietic stem cells in murine myelodysplastic syndrome. Proc Natl Acad Sci U S A 107:9783-8 |
| Laricchia-Robbio, Leopoldo; Premanand, Kavitha; Rinaldi, Ciro R et al. (2009) EVI1 Impairs myelopoiesis by deregulation of PU.1 function. Cancer Res 69:1633-42 |
| Senyuk, Vitalyi; Rinaldi, Ciro Roberto; Li, Donglan et al. (2009) Consistent up-regulation of Stat3 Independently of Jak2 mutations in a new murine model of essential thrombocythemia. Cancer Res 69:262-71 |
| Cattaneo, Francesca; Nucifora, Giuseppina (2008) EVI1 recruits the histone methyltransferase SUV39H1 for transcription repression. J Cell Biochem 105:344-52 |
| Senyuk, Vitalyi; Sinha, Kislay K; Li, Donglan et al. (2007) Repression of RUNX1 activity by EVI1: a new role of EVI1 in leukemogenesis. Cancer Res 67:5658-66 |
| Li, Donglan; Sinha, Kislay K; Hay, Maher A et al. (2007) RUNX1-RUNX1 homodimerization modulates RUNX1 activity and function. J Biol Chem 282:13542-51 |
| Nucifora, Giuseppina; Laricchia-Robbio, Leopoldo; Senyuk, Vitalyi (2006) EVI1 and hematopoietic disorders: history and perspectives. Gene 368:1-11 |
| Mikhail, Fady M; Sinha, Kislay K; Saunthararajah, Yogen et al. (2006) Normal and transforming functions of RUNX1: a perspective. J Cell Physiol 207:582-93 |
| Saunthararajah, Yogen; Boccuni, Piernicola; Nucifora, Giuseppina (2006) Combinatorial action of RUNX1 and PU.1 in the regulation of hematopoiesis. Crit Rev Eukaryot Gene Expr 16:183-92 |
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