University of Veterinary Medicine, Vienna, Vienna, Austria.
Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Graz, Austria.
Blood. 2024 Jul 11;144(2):156-170. doi: 10.1182/blood.2023021985.
Hematopoietic stem cells (HSCs) are characterized by the ability to self-renew and to replenish the hematopoietic system. The cell-cycle kinase cyclin-dependent kinase 6 (CDK6) regulates transcription, whereby it has both kinase-dependent and kinase-independent functions. Herein, we describe the complex role of CDK6, balancing quiescence, proliferation, self-renewal, and differentiation in activated HSCs. Mouse HSCs expressing kinase-inactivated CDK6 show enhanced long-term repopulation and homing, whereas HSCs lacking CDK6 have impaired functionality. The transcriptomes of basal and serially transplanted HSCs expressing kinase-inactivated CDK6 exhibit an expression pattern dominated by HSC quiescence and self-renewal, supporting a concept, in which myc-associated zinc finger protein (MAZ) and nuclear transcription factor Y subunit alpha (NFY-A) are critical CDK6 interactors. Pharmacologic kinase inhibition with a clinically used CDK4/6 inhibitor in murine and human HSCs validated our findings and resulted in increased repopulation capability and enhanced stemness. Our findings highlight a kinase-independent role of CDK6 in long-term HSC functionality. CDK6 kinase inhibition represents a possible strategy to improve HSC fitness.
造血干细胞（HSCs）的特征是自我更新和补充造血系统的能力。细胞周期蛋白依赖性激酶 6（CDK6）调节转录，具有激酶依赖性和激酶非依赖性功能。本文描述了 CDK6 的复杂作用，它在激活的 HSCs 中平衡静止、增殖、自我更新和分化。表达激酶失活 CDK6 的小鼠 HSCs 显示出增强的长期重殖和归巢能力，而缺乏 CDK6 的 HSCs 则表现出功能受损。表达激酶失活 CDK6 的基础和连续移植 HSCs 的转录组表现出以 HSC 静止和自我更新为主导的表达模式，支持 myc 相关锌指蛋白 (MAZ) 和核转录因子 Y 亚基α (NFY-A) 是关键 CDK6 相互作用蛋白的概念。用临床使用的 CDK4/6 抑制剂在鼠和人 HSCs 中进行的激酶抑制药理学实验验证了我们的发现，并导致了更高的重殖能力和增强的干细胞特性。我们的发现强调了 CDK6 在长期 HSC 功能中的激酶非依赖性作用。CDK6 激酶抑制可能是提高 HSC 适应性的一种策略。
