A06: Erlacher

Juvenile myelomonocytic leukemia (JMML), an aggressive chronic leukemia of early childhood, is caused by mutations in the genes coding for KRAS, NRAS or their regulators NF1, CBL or PTPN11. PTPN11 codes for the phosphatase SHP2 and is responsible for the most aggressive JMML subtype. Only few second hit mutations are involved, making JMML and related genetically modified mouse models (GEMMs) suitable models to study signaling changes imposed by constitutively active RAS. In a JMML-GEMM characterized by expression of an oncogenic SHP2 mutant in the hematopoietic system, we found that apoptosis resistance is a consistent feature of leukemic monocytes and granulocytes. Preliminary findings indicate that death/survival decisions are affected in a cell type-specific manner. In both leukemic monocytes and granulocytes, apoptosis resistance correlates with higher protein levels of BCL-x_L and MCL-1. However, while leukemic monocytes show increased sensitivity towards BCL-x_L inhibition, leukemic granulocytes are sensitive selectively to MCL-1 inhibition. It is the aim of this project to characterize death-survival decisions in different leukemic cell types with focus on oncogenic, developmental and cell-extrinsic signals. In the first part, we will elucidate how BCL-x_L and MCL-1 are regulated in leukemic monocytes and granulocytes. In the second part, we will characterize the expression and activation of other BCL-2 proteins. Finally, we will analyse the effects of different pro-apoptotic drugs on the cell death decision to identify synthetic lethal combinations. We expect that understanding the apoptotic machinery of different JMML cell types will shed light on cell type-specific effects of RAS-survival signalling and open the way for novel therapeutic approaches for JMML.