Abemaciclib drives the therapeutic differentiation of acute myeloid leukaemia stem cells

癌症研究 髓样 干细胞 医学 细胞周期蛋白依赖激酶 分化疗法 药理学 细胞周期 生物 免疫学 内科学 癌症 细胞培养 遗传学 急性早幼粒细胞白血病 维甲酸
作者
Xiaoling Xie,Wuju Zhang,Xuan Zhou,Zhixin Ye,Hao Wang,Qiu Yu-chang,Yating Pan,Ya-Han Hu,Luyao Li,Zhuanzhuan Chen,Wanwen Yang,Yao Lu,Shuxin Zou,Yuhua Li,Xia Bai
出处
期刊:British Journal of Haematology [Wiley]
卷期号:201 (5): 940-953 被引量:1
标识
DOI:10.1111/bjh.18735
摘要

Self-renewal and differentiation arrest are two features of leukaemia stem cells (LSCs) responsible for the high relapse rate of acute myeloid leukaemia (AML). To screen drugs to overcome differentiation blockade for AML, we conducted screening of 2040 small molecules from a library of United States Food and Drug Administration-approved drugs and found that the cyclin-dependent kinase (CDK)4/6 inhibitor, abemaciclib, exerts high anti-leukaemic activity. Abemaciclib significantly suppressed proliferation and promoted the differentiation of LSCs in vitro. Abemaciclib also efficiently induced differentiation and impaired self-renewal of LSCs, thus reducing the leukaemic cell burden and improving survival in various preclinical animal models, including patient-derived xenografts. Importantly, abemaciclib strongly enhanced anti-tumour effects in combination with venetoclax, a B-cell lymphoma 2 (Bcl-2) inhibitor. This treatment combination led to a marked decrease in LSC-enriched populations and resulted in a synergistic anti-leukaemic effect. Target screening revealed that in addition to CDK4/6, abemaciclib bound to and inhibited CDK9, consequently attenuating the protein levels of global p-Ser2 RNA Polymerase II (Pol II) carboxy terminal domain (CTD), Myc, Bcl-2, and myeloid cell leukaemia-1 (Mcl-1), which was important for the anti-AML effect of abemaciclib. Collectively, these data provide a strong rationale for the clinical evaluation of abemaciclib to induce LSC differentiation and treat highly aggressive AML as well as other advanced haematological malignancies.
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