Inhibition of the anti-apoptotic protein MCL-1 severely suppresses human hematopoiesis

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 approved by the Food and Drug Administration, 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 RNA interference 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 hematopoietic stem and progenitor cells already at inhibitor concentrations of 0.1 mu M each, indicating synthetic lethality of the two BH3-mimetics in the hematopoietic system.

Automated summary

Inhibition of MCL-1 has a significant impact on the human hematopoietic system, depleting hematopoietic stem and progenitor cells and restricting their differentiation potential. Mature blood cells survive normally in the absence of MCL-1, but CD34(+) cells show limited engraftment potential upon xenotransplantation. Combined inhibition of MCL-1 and BCL-XL results in synergistic effects, causing loss of hematopoietic stem and progenitor cells.