Project P9

"Characterization of survival signals essential for the maintenance of human hematopoiesis"

People involved: Miriam Erlacher, Sheila Bohler

Abstract:
Myelosuppression is a frequent and often dose-limiting side effect of anticancer therapy and associated with significant treatment-related morbidity. Since most chemotherapeutic regimens rely on full hematopoietic regeneration after transient aplasia, a better knowledge of human hematopoietic stem cells and their minimal requirements to survive and to maintain or regenerate the hematopoietic system is required. Thus, we here aim to identify proteins and signaling pathways essentially required for stem cell survival.
Based on data from mouse models it is anticipated, but not formally proven, that the pro-survival Bcl-2 family members Mcl-1 and Bcl-xL are essential for hematopoietic stem and progenitor cell (HSPCs) survival in humans. Given the intense efforts aiming to develop selective inhibitors of pro-survival Bcl-2 family members, i.e. so-called BH3-mimetics, it is essential to define the vulnerabilities of human HSPCs upon inhibition of individual Bcl-2 family proteins, either per se, or in combination with frequently used anticancer agents.
By using RNAi based ablation of gene expression in cord blood-derived CD34+ HSPCs we will study which pro-survival Bcl-2 protein or their combination are essential for human HSPC survival, and which upstream signaling pathways contribute to their expression. Additionally, by simultaneous inhibition of their antagonists, the BH3-only proteins, we intend to rescue CD34+ cells from death, thereby identifying BH3-only proteins limiting the lifespan of human HSCPs. Finally, we will analyze whether tolerance of human HSPCs to clinically applied cytotoxic agents is affected by an altered Bcl-2 rheostat.
Our studies will complement our knowledge on apoptosis signaling in human HSPCs and help to depict critical limits of stress resistance within the hematopoietic system, which should not be breached in combination therapies used for anticancer treatment.

Co-operations within FOR2036:
Andreas Villunger, Innsbruck, Austria
Alexander Egle, Salzburg, Austria
Philipp Jost, Muenchen, Germany