MDM2 antagonist improves therapeutic activity of azacitidine in myelodysplastic syndromes and chronic myelomonocytic leukemia

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.

Keywords:

• Myelodysplastic syndromes
• chronic myelomonocytic leukemia
• hypomethylating agent
• MDM2
• TP53

Acknowledgements

We thank MDACC Cell Imaging and Flow Cytometry Core for analyzing cell line and mouse bone marrow samples.

Disclosure statement

The authors declare no competing interests.

Additional information

Funding

We thank Daiichi Sanko Pharmaceutical Company for the financial support. This work was supported in part by the Daiichi-Sankyo MD Anderson Research Alliance, the University of Texas MD Anderson Cancer Center Support Grant CA016672, and the University of Texas MD Anderson Cancer Center MDS/AML Moon Shot.