Inhibition of the anti-apoptotic protein MCL-1 severely suppresses human hematopoiesis
Haematologica
; 106(12): 3136-3148, 2021 12 01.
Article
em En
| MEDLINE
| ID: mdl-33241675
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Proto-Oncogênicas c-bcl-2
/
Proteínas Reguladoras de Apoptose
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Haematologica
Ano de publicação:
2021
Tipo de documento:
Article