Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, China.
Pharmacol Res. 2020 Jan;151:104545. doi: 10.1016/j.phrs.2019.104545. Epub 2019 Nov 15.
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 both in vitro and in 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.
白血病细胞的一个特征是细胞成熟过程中的分化阻滞。全反式维甲酸（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，研究延长基于 ATRA 的治疗对非 APL AML 的疗效的策略是一个关键的研究途径。在这里，我们评估了 CDK2 抑制和 ATRA 在 AML 中的体外和体内协同作用。我们已经确定 CDK2 的耗竭和 CDK2 的药理学抑制剂都能显著增强三种 AML 细胞（包括两种非 APL 细胞）对 ATRA 诱导的细胞分化的敏感性。RNA 测序结果表明，分化和成熟途径的转录激活在这种协同作用中起着重要作用。此外，下调 CDK2 可使 AML 细胞对 ATRA 诱导的植入物预防 NOD-SCID 小鼠中的白血病细胞和促进与 ATRA 联合使用时的原始 AML 母细胞分化敏感。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，而且还揭示了 CDK2 抑制剂在基于 ATRA 的 AML 分化治疗中的未来临床应用。
