Mechanisms of aberrant transcription of EVI1 in acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2).

• Applicant: Privatdozent Dr. Stefan Gröschel
• Subject Area: Hematology, Oncology
• Term: from 2011 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 205982662

Acute myeloid leukemia (AML) defines a clonal neoplastic disease of bone marrow blasts with heterogeneous underlying genetic and epigenetic aberrations and with very different responses to therapy. Patients with AML and chromosomal abnormalities inv(3)(q21q26.2) or t(3;3)(q21;q26.2) [inv(3)/t(3;3)] have a dismal prognosis. These aberrations give rise to an excessive expression of the proto-oncogen EVI1, which maps to chromosomal band 3q26.2 and which can cause leukemic transformation of myeloid progenitor cells upon activation. EVI1 transcripts are absent or undetectably low in normal hematopoietic progenitors and most other AML subtypes. Knock-down of EVI1 in AML blasts with 3q26 aberrations and high EVI1 expression leads to a severe reduction of proliferation in vitro. Both chromosomal breaks at 3q26 in AML with inv(3) or t(3;3) are associated with a translocation of another gene called RPN1 directly into close proximity of the EVI1 locus. Aim of this project is to study the mechanisms of aberrant transcriptional control of the EVI1 gene in AML with inv(3)/t(3;3). Firstly, we wish to identify the regulatory elements in RPN1 and EVI1 and the combination of transcription factors required for aberrant transcription of EVI1. Finally, we plan to study how we can interfere with the transcriptional control of EVI1 as a possible target for future therapies using reporter constructs and inv(3)/t(3;3) AML cell models.

• DFG Programme: Research Fellowships
• International Connection: Netherlands
• Host: Professor Ruud Delwel, Ph.D.