MDM2 antagonist improves therapeutic activity of azacitidine in myelodysplastic syndromes and chronic myelomonocytic leukemia.
Leuk Lymphoma
; 63(13): 3154-3164, 2022 12.
Article
em En
| MEDLINE
| ID: mdl-36059252
ABSTRACT
Failure of hypomethylation agent (HMA) treatments is an important issue in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Recent studies indicated that function of wildtype TP53 positively impacts outcome of HMA treatments. We investigated the combination of the HMA azacitidine (AZA) with DS-3032b and DS-5272, novel antagonists of the TP53 negative regulator MDM2, in cellular and animal models of MDS and CMML. In TP53 wildtype myeloid cell line, combinational effects of DS-3032b or DS-5272 with AZA were observed. In Tet2-knockout mouse model of MDS and CMML, DS-5272 and AZA combination ameliorated disease-like phenotype. RNA-Seq analysis in mouse bone marrow hematopoietic stem and progenitors indicated that DS-5272 and AZA combination caused down-regulation of leukemia stem cell marker genes and activation of pathways of TP53 function and stability. These findings demonstrate that combining an MDM2 antagonist with AZA has potential to improve AZA treatment in TP53 wildtype MDS and CMML.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Síndromes Mielodisplásicas
/
Leucemia Mielomonocítica Crônica
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Leuk Lymphoma
Assunto da revista:
HEMATOLOGIA
/
NEOPLASIAS
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos