Differentiation therapy based on ATRA almost cured acute promyelocytic leukemia (APL). However, it is disappointing that ATRA is not effective against other acute myeloid leukemia (AML) subtypes. Developing new and effective anti-AML therapies that promote leukemia differentiation is necessary. The CDK4/6-cyclin D pathway is a key initiator of the G1/S phase transition, which determines cell fate. Herein, we investigated whether the CDK4/6 inhibitor palbociclib would synergize with ATRA to promote leukemia differentiation in vitro and in vivo. Our findings revealed that CDK4/6-cyclin D pathway genes were aberrantly expressed in AML, and we observed that palbociclib sensitized AML cells to ATRA-induced morphologic, biochemical, and functional changes indicative of myeloid differentiation. The combination of palbociclib and ATRA attenuated AML cell expansion in vivo. These enhanced differentiation effects may be associated with the regulation of transcription factors, including RARα, E2F1, and STAT1. Overall, our findings demonstrate that CDK4/6 inhibition sensitizes AML cells to ATRA and could guide the development of novel therapeutic strategies for AML patients.

中文翻译：

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CDK4/6 抑制剂 Palbociclib 与 ATRA 协同诱导 AML 分化

基于ATRA的分化治疗几乎治愈了急性早幼粒细胞白血病（APL）。然而，令人失望的是，ATRA 对其他急性髓系白血病 (AML) 亚型无效。有必要开发新的有效的抗 AML 疗法来促进白血病分化。 CDK4/6-cyclin D 通路是决定细胞命运的 G1/S 相变的关键启动子。在此，我们研究了 CDK4/6 抑制剂 palbociclib 是否会与 ATRA 协同作用，在体外和体内促进白血病分化。我们的研究结果表明，CDK4/6-cyclin D 通路基因在 AML 中异常表达，并且我们观察到 palbociclib 使 AML 细胞对 ATRA 诱导的形态、生化和功能变化（表明骨髓分化）敏感。 palbociclib 和 ATRA 的组合可减弱体内 AML 细胞的增殖。这些增强的分化效应可能与转录因子的调节有关，包括 RARα、E2F1 和 STAT1。总的来说，我们的研究结果表明，CDK4/6 抑制使 AML 细胞对 ATRA 敏感，并可以指导针对 AML 患者开发新的治疗策略。