MDM2 拮抗剂可提高阿扎胞苷治疗骨髓增生异常综合征和慢性粒单核细胞白血病的疗效。
MDM2 antagonist improves therapeutic activity of azacitidine in myelodysplastic syndromes and chronic myelomonocytic leukemia.
机构信息
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
出版信息
Leuk Lymphoma. 2022 Dec;63(13):3154-3164. doi: 10.1080/10428194.2022.2116932. Epub 2022 Sep 5.
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 wildtype myeloid cell line, combinational effects of DS-3032b or DS-5272 with AZA were observed. In -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 wildtype MDS and CMML.
低甲基化药物（HMA）治疗失败是骨髓增生异常综合征（MDS）和慢性粒单核细胞白血病（CMML）的一个重要问题。最近的研究表明，野生型 TP53 的功能对 HMA 治疗的结果有积极影响。我们研究了 HMA 阿扎胞苷（AZA）与 DS-3032b 和 DS-5272 的联合应用，这两种药物是 TP53 负调节剂 MDM2 的新型拮抗剂，在 MDS 和 CMML 的细胞和动物模型中进行了研究。在野生型髓系细胞系中，观察到 DS-3032b 或 DS-5272 与 AZA 的联合作用。在 MDS 和 CMML 的 -/- 敲除小鼠模型中，DS-5272 和 AZA 联合改善了疾病样表型。对小鼠骨髓造血干细胞和祖细胞的 RNA-Seq 分析表明，DS-5272 和 AZA 联合导致白血病干细胞标记基因的下调和 TP53 功能和稳定性途径的激活。这些发现表明，将 MDM2 拮抗剂与 AZA 联合使用有可能改善野生型 MDS 和 CMML 中 AZA 的治疗效果。
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