Juvenile myelomonocytic leukemia (JMML) is a very aggressive myeloproliferative neoplasia of early childhood. The most aggressive subtype is caused by mutations in PTPN11 coding for SHP2 that lead to activation of the RAS/MAPK, PI3K/AKT and Rho signaling pathways. Apoptosis deregulation is an important hallmark in leukemia and it is known that apoptosis-resistant cells are selected during malignant transformation. We have a special interest in the BCL-2 protein family that consists of pro- and anti-apoptotic members. It is known that RAS activation increases cell survival by regulating BCL-2 proteins but it is unclear whether and how BCL-2 proteins are involved in the different stages of RAS driven transformation. To address this, we use PTPN11 knockin mice prone to myeloproliferation and leukemia to investigate the regulation and roles of anti- and pro-apoptotic BCL-2 proteins before, during and upon malignant transformation. We are analyzing BCL-2 protein regulation and apoptotic susceptibility in differentiated myeloid and monocytic cells as well as in stem and progenitor cells, and testing BH3-mimetics for their therapeutic potential in patients with JMML.
