Combined Drug Targeting of p53-dependent and -independent Pathways Depletes Myelofibrosis Hematopoietic Stem/Progenitor Cells.
Leukemia
; 36(3): 733-745, 2022 03.
Article
em En
| MEDLINE
| ID: mdl-34642468
ABSTRACT
Current therapy for myelofibrosis (MF) results in a limited prolongation of patient survival. In order to improve treatment outcomes, we developed a strategy to effectively deplete MF hematopoietic stem/progenitor cells (HSPCs). In the present study, an imipridone, ONC201, was combined with RG7112, an antagonist of MDM2, a p53 negative regulator, to activate downstream events of the p53 and TNF-related apoptosis-inducing ligand (TRAIL)/death receptor (DR) pathways. As compared to treatment with the individual drugs, the combination of ONC201 and RG7112 promoted greater degrees of apoptosis of MF CD34+ cells through activation of both p53-dependent and -independent pathways. Importantly, treatment with ONC201-RG7112 not only decreased the number of JAK2V617F+ and calreticulin mutated colonies assayed from MF CD34+ cells, but allowed for the persistence or appearance of JAK2 wild type colonies. Treatment with ONC201 combined with RG7112 could be a potentially effective strategy for treating MF patients.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piridinas
/
Pirimidinas
/
Células-Tronco Hematopoéticas
/
Proteína Supressora de Tumor p53
/
Imidazolinas
/
Mielofibrose Primária
/
Imidazóis
/
Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Leukemia
Assunto da revista:
HEMATOLOGIA
/
NEOPLASIAS
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos