Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA096448-01
Application #
6493200
Study Section
Special Emphasis Panel (ZRG1-MEP (02))
Program Officer
Mufson, R Allan
Project Start
2001-09-24
Project End
2005-08-31
Budget Start
2001-09-24
Budget End
2002-08-31
Support Year
1
Fiscal Year
2001
Total Cost
$280,566
Indirect Cost

  Institution

Name
University of Illinois at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612

  Publications

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
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
Laricchia-Robbio, Leopoldo; Fazzina, Raffaella; Li, Donglan et al. (2006) Point mutations in two EVI1 Zn fingers abolish EVI1-GATA1 interaction and allow erythroid differentiation of murine bone marrow cells. Mol Cell Biol 26:7658-66
Nucifora, Giuseppina; Laricchia-Robbio, Leopoldo; Senyuk, Vitalyi (2006) EVI1 and hematopoietic disorders: history and perspectives. Gene 368:1-11

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