HCK maintains the self-renewal of leukaemia stem cells via CDK6 in AML.
HCK maintains the self-renewal of leukaemia stem cells via CDK6 in AML.
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HCK在AML中通过CDK6维持白血病干细胞的自我更新
DOI：
10.1186/s13046-021-02007-4
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发表时间：
2021-06-24
期刊：
影响因子：
--
通讯作者：
Liang A
中科院分区：
文献类型：
--
作者：
Li Z;Wang F;Tian X;Long J;Ling B;Zhang W;Xu J;Liang A
背景白血病干细胞（Leukaemia stem cells，LSC）是急性髓细胞白血病（acute myeloid leukaemia，AML）的发生、维持和复发的重要因素。确定治疗LSC的目标是至关重要的治愈AML.MethodsBioinformatics数据库被用来确定治疗LSC的目标。用条件性基因敲除小鼠分析HCK在白血病发生和正常造血中的作用。集落形成试验、细胞计数和流式细胞术用于检测白血病细胞的活力和功能。RT-PCR、Western blotting和RNA测序检测mRNA和蛋白表达。ResultHCK在LSC中的表达水平高于造血干细胞（HSC），高水平的HCK表达与AML患者生存时间缩短相关。HCK的敲低导致细胞周期停滞，这导致人AML细胞系中增殖和集落形成的急剧减少。此外，HCK是体内和体外白血病发生和白血病维持所必需的。在连续移植和有限稀释实验中，HCK是LSC自我更新所必需的。由HCK缺陷引起的表型可以通过CDK 6在人细胞系中的过表达来挽救。RNA测序和基因表达研究表明，HCK可通过激活ERK 1/2-c-Myc-CDK 6信号轴维持LSC进入细胞周期和自我更新能力。与此相反，HCK缺失不影响正常的造血或造血重建在mice.ConclusionsHCK通过CDK 6在AML中维持白血病干细胞的自我更新，可能是一个理想的治疗靶点，用于根除LSC而不影响正常的造血。
BackgroundLeukaemia stem cells (LSCs) are responsible for the initiation, maintenance, and recurrence of acute myeloid leukaemia (AML), an aggressive haematological malignancy associated with drug resistance and relapse. Identifying therapeutic LSC targets is critical to curing AML.MethodsBioinformatics databases were used to identify therapeutic LSC targets. The conditional knockout mice were used to analyse the role of HCK in leukaemogenesis or normal haematopoiesis. Colony-forming assays, cell counting, and flow cytometry were used to detect the viability and function of leukaemia cells. RT-PCR, western blotting, and RNA sequencing were used to detect mRNA and protein expression.ResultHCK is expressed at higher levels in LSCs than in haematopoietic stem cells (HSCs), and high HCK levels are correlated with reduced survival time in AML patients. Knockdown of HCK leads to cell cycle arrest, which results in a dramatic decrease in the proliferation and colony formation in human AML cell lines. Moreover, HCK is required for leukemogenesis and leukaemia maintenance in vivo and in vitro. HCK is necessary for the self-renewal of LSCs during serial transplantation and limiting dilution assay. The phenotypes resulting from HCK deficiency can be rescued by CDK6 overexpression in the human cell line. RNA sequencing and gene expression have demonstrated that HCK may sustain cell cycle entry and maintain the self-renewal ability of LSCs through activating the ERK1/2-c-Myc-CDK6 signalling axis. In contrast, HCK deletion does not affect normal haematopoiesis or haematopoietic reconstruction in mice.ConclusionsHCK maintains the self-renewal of leukaemia stem cells via CDK6 in AML and may be an ideal therapeutic target for eradicating LSCs without influencing normal haematopoiesis.
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