Characterization of survival signals essential for the maintenance of human hematopoiesis

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 are studying 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 are analyzing 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.

Projektbeginn: 01.03.2014
Projektende: 28.02.2017

Miriam Erlachr

Albert-Ludwigs-Universität Freiburg
Zentrum für Kinder- und Jugendmedizin (Department)
Klinik für Pädiatrische Hämatologie und Onkologie
Mathildenstrasse 1
79106 Freiburg

Telefon: +49 761 270 45060
Fax: +49761270 45180
Email: zkj-onkpaed@uniklinik-freiburg.de
https://www.uniklinik-freiburg.de/paed-haematologie.html