CDK2 suppression synergizes with all-trans-retinoic acid to overcome the myeloid differentiation blockade of AML cells.
CDK2 suppression synergizes with all-trans-retinoic acid to overcome the myeloid differentiation blockade of AML cells.
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DOI：
10.1016/j.phrs.2019.104545
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发表时间：
2019-11
影响因子：
9.3
通讯作者：
Xuejing Shao;Sen-feng Xiang;Huarui Fu;Ying-qian Chen;Aixiao Xu;Yujia Liu;Xiaotian Qi;Ji Cao;Hong Zhu;Bo Yang;Qiaojun He;Meidan Ying
中科院分区：
文献类型：
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作者：
Xuejing Shao;Sen-feng Xiang;Huarui Fu;Ying-qian Chen;Aixiao Xu;Yujia Liu;Xiaotian Qi;Ji Cao;Hong Zhu;Bo Yang;Qiaojun He;Meidan Ying
白血病细胞的一个特征是在细胞成熟过程中阻滞分化。全反式维甲酸（All-trans-retinoic acid， ATRA）已成功应用于治疗m3型AML (APL, 10%)，但对其余非APL AML患者（90%）未能显示出显著疗效。因此，将基于atra的治疗效果扩展到非apl AML的策略研究是一个关键的研究途径。在这里，我们在体外和体内评估CDK2抑制和ATRA在AML中的协同作用。我们已经确定CDK2耗竭和CDK2药理学抑制剂都显著使三种亚型AML细胞（包括两种非apl细胞）对atra诱导的细胞分化敏感。rna序列结果表明，分化和成熟途径的转录激活在这种协同效应中起重要作用。此外，在NOD-SCID小鼠中，CDK2的下调使AML细胞敏感于ATRA诱导的白血病细胞植入预防，并在与ATRA联合时促进原发性AML细胞分化。因此，我们的工作不仅为进一步验证CDK2作为分化治疗靶点提供了相关的实验证据，而且揭示了CDK2抑制剂在基于atra的AML分化治疗中的未来临床应用。
A characteristic feature of leukemia cells is a blockade of differentiation in cellular maturation. All-trans-retinoic acid (ATRA) has been successfully applied for the treatment of M3-type AML (APL, 10 %), but it fails to demonstrate a significant efficacy on the remaining patients with non-APL AML (90 %). Therefore, the research for strategies to extend the efficacy of ATRA-based therapy to non-APL AML is a key avenue of investigation. Here, we evaluate the synergetic effect of CDK2 inhibition and ATRA in AML bothin vitroandin vivo. We have determined that both the CDK2 depletion and pharmacological inhibitor of CDK2 significantly sensitize three subtypes of AML cells (including two non-APL cells) to ATRA-induced cell differentiation. RNA-sequence results indicate that transcription activation of differentiation and maturation pathways plays an important role in this synergetic effect. Furthermore, the down-regulation of CDK2 sensitized AML cells to ATRA-induced engraftment prevention of leukemia cells in NOD-SCID mice and promotes the primary AML blasts differentiation when combined with ATRA. Thus, our work not only provides relevant experimental evidence for further validating CDK2 as a target for differentiation therapy, but also uncovers the future clinical application of CDK2 inhibitors in ATRA-based differentiation therapeutics for AML.