Characterization of pro- and anti-apoptotic Bcl-2 proteins regulating hematopoiesis and leukemogenesis in the context of RAS hyperactivation

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Pro- and anti-apoptotic members of the Bcl-2 protein family and their balanced regulation are of crucial importance for generation, maintenance and function of the hematopoietic system. Although reasonably well defined in the mouse hematopoietic system, the many roles of Bcl-2 proteins in human hematopoiesis are still incompletely understood. In the current funding period, we are therefore investigating how Bcl-2 proteins contribute to proper functioning of the human hematopoietic system. We are focusing on pro-survival Bcl-2 proteins to identify the protein or protein combinations that are required to keep human hematopoietic stem and progenitor cells alive, both under steady state conditions and when put under stress. By doing so, we aim at defining the "minimal requirements" for stem cell survival and blood formation. In the follow-up project, we will investigate how composition and regulation of Bcl-2 proteins do change during malignant transformation. As a model system for the multistep process of tumorigenesis, we will use cells with constitutively activated RAS signaling. Constitutively activated RAS signaling (e.g. due to mutations in NRAS, KRAS, PTPN11, NF1 or CBL) in hematopoietic cells can either result in an apparently unaffected hematopoiesis (i.e. in patients with Noonan syndrome) or in polyclonal and transient myeloproliferation, as seen in a subset of Noonan syndrome patients. It can, however, also result in juvenile myelomonocytic leukemia (JMML), a highly aggressive myeloid childhood leukemia. Using cells derived from patients with Noonan syndrome (+/- myeloproliferation) or JMML, as well as corresponding mouse models, we propose to characterize if and how Bcl-2 proteins are deregulated in different stages of RAS-driven leukemic transformation and evaluate, in which disease stages it could be beneficial to treat patients with BH3-mimetics. We hypothesize that the profile of Bcl-2 protein deregulation changes during disease progression and that these changes contribute to the pathogenesis of myeloproliferation and JMML. We expect that these results will be transferable to some extent from Noonan syndrome, myeloproliferation and JMML to more complex types of cancer that are also driven by RAS activation.