TY - JOUR
T1 - MDM2 antagonist improves therapeutic activity of azacitidine in myelodysplastic syndromes and chronic myelomonocytic leukemia
AU - Wei, Yue
AU - Zheng, Hong
AU - Lockyer, Pamela Pennington
AU - Darbaniyan, Faezeh
AU - Li, Ziyi
AU - Kanagal-Shamanna, Rashmi
AU - Soltysiak, Kelly A.
AU - Yang, Hui
AU - Ganan-Gomez, Irene
AU - Montalban-Bravo, Guillermo
AU - Chien, Kelly S.
AU - Do, Kim Anh
AU - Daver, Naval
AU - Garcia-Manero, Guillermo
N1 - Publisher Copyright:
© 2022 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - chronic myelomonocytic leukemia
KW - hypomethylating agent
KW - MDM2
KW - Myelodysplastic syndromes
KW - TP53
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U2 - 10.1080/10428194.2022.2116932
DO - 10.1080/10428194.2022.2116932
M3 - Article
C2 - 36059252
AN - SCOPUS:85137817486
SN - 1042-8194
VL - 63
SP - 3154
EP - 3164
JO - Leukemia and Lymphoma
JF - Leukemia and Lymphoma
IS - 13
ER -