Author:
Bohler Sheila,Afreen Sehar,Fernandez-Orth Juncal,Demmerath Eva-Maria,Molnar Christian,Wu Ying,Weiss Julia Miriam,Mittapalli Venugopal Rao,Konstantinidis Lukas,Schmal Hagen,Kunze Mirjam,Erlacher Miriam
Abstract
BH3-mimetics inhibiting anti-apoptotic BCL-2 proteins represent a novel and promising class of antitumor drugs. While the BCL-2 inhibitor venetoclax is already FDA-approved, BCL-XL and MCL-1 inhibitors are currently in early clinical trials. To predict side effects of therapeutic MCL-1 inhibition on the human hematopoietic system, we used RNAi and the small molecule inhibitor S63845 on cord blood-derived CD34+ cells. Both approaches resulted in almost complete depletion of human hematopoietic stem and progenitor cells. As a consequence, maturation into the different hematopoietic lineages was severely restricted and CD34+ cells expressing MCL-1 shRNA showed a very limited engraftment potential upon xenotransplantation. In contrast, mature blood cells survived normally in the absence of MCL-1. Combined inhibition of MCL-1 and BCL-XL resulted in synergistic effects with relevant loss of colony-forming HSPCs already at inhibitor concentrations of 0.1 μM each, indicating “synthetic lethality” of the two BH3-mimetics in the hematopoietic system.
Publisher
Ferrata Storti Foundation (Haematologica)
Cited by
17 articles.
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