Functional screen of genes on chromosome 7q that contribute to the pathogenesis of myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML) and to the response to hypomethylating agents

The myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal, pre-leukemic disorders characterized by ineffective hematopoiesis. One clinical feature of MDS is the frequent progression to acute myeloid leukemia (AML), which is a leading cause of death in these patients. These so-called secondary AML (sAML) are characterized by relative resistance to standard chemotherapy and an adverse prognosis. Recent studies with azacytidine revealed that MDS patients with deletions on the long arm of 7q (7q-) seem to benefit from treatment with hypomethylating agents to a greater degree than other MDS patients. 7q- is a recurrent aberration in MDS and AML but the corresponding deleted gene or genes that lead to a clonal dominance of the affected cells remain unknown. In the proposed project we aim to identify the responsible genes by using an RNA interference screen. To determine the molecular basis for the specific cell toxicity from hypomethylating agents we will perform an RNA interference screen of 7q genes in the presence of decitabine in the second part of this project. Finally, known mutations in MDS/ sAML will be characterized functionally by lentiviral transduction of shRNAs or mutated cDNAs.

DFG Programme Research Fellowships

International Connection USA

Host Professor Dr. Benjamin L. Ebert