Leukemia stem cells (LSCs) in individuals with chronic myelogenous leukemia (CML) (hereafter referred to as CML LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR-ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here we show that although the microRNA (miRNA) miR-126 supported the quiescence, self-renewal and engraftment capacity of CML LSCs, miR-126 levels were lower in CML LSCs than in long-term hematopoietic stem cells (LT-HSCs) from healthy individuals. Downregulation of miR-126 levels in CML LSCs was due to phosphorylation of Sprouty-related EVH1-domain-containing 1 (SPRED1) by BCR-ABL, which led to inhibition of the RAN-exportin-5-RCC1 complex that mediates miRNA maturation. Endothelial cells (ECs) in the BM supply miR-126 to CML LSCs to support quiescence and leukemia growth, as shown using mouse models of CML in which Mir126a (encoding miR-126) was conditionally knocked out in ECs and/or LSCs. Inhibition of BCR-ABL by TKI treatment caused an undesired increase in endogenous miR-126 levels, which enhanced LSC quiescence and persistence. Mir126a knockout in LSCs and/or ECs, or treatment with a miR-126 inhibitor that targets miR-126 expression in both LSCs and ECs, enhanced the in vivo anti-leukemic effects of TKI treatment and strongly diminished LSC leukemia-initiating capacity, providing a new strategy for the elimination of LSCs in individuals with CML.

中文翻译：

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miR-126的骨髓生境运输控制慢性粒细胞性白血病中白血病干细胞的自我更新。

患有慢性粒细胞性白血病（CML）的个体中的白血病干细胞（LSC）（以下称为CML LSC）负责引发和维持克隆性造血功能。尽管酪氨酸激酶抑制剂（TKIs）有效抑制了BCR-ABL激酶活性，但这些细胞仍存在于骨髓（BM）中。在这里，我们显示，尽管microRNA（miRNA）miR-126支持CML LSC的静止，自我更新和移植能力，但CML LSC中的miR-126水平低于来自CML LSC的长期造血干细胞（LT-HSC）健康的个体。CML LSCs中miR-126水平的下调是由于BCR-ABL对Sprouty相关的含EVH1域的1（SPRED1）的磷酸化，导致对介导miRNA成熟的RAN-exportin-5-RCC1复合物的抑制。BM中的内皮细胞（EC）向CML LSC提供miR-126以支持静止和白血病生长，如使用CML小鼠模型所显示的，其中在Mirs中有条件地敲除Mir126a（编码miR-126）的EC和/或LSC。TKI处理对BCR-ABL的抑制作用导致内源性miR-126水平异常增加，从而增强了LSC的静止性和持久性。LSC和/或EC中的Mir126a敲除，或用靶向LSC和EC中miR-126表达的miR-126抑制剂治疗，可增强TKI治疗的体内抗白血病作用，并大大降低LSC的白血病启动能力，从而提供消除CML患者LSC的新策略。如使用CML小鼠模型所示，其中在EC和/或LSC中有条件地敲除了Mir126a（编码miR-126）。TKI处理对BCR-ABL的抑制作用导致内源性miR-126水平异常增加，从而增强了LSC的静止性和持久性。LSC和/或EC中的Mir126a敲除，或用靶向LSC和EC中miR-126表达的miR-126抑制剂治疗，可增强TKI治疗的体内抗白血病作用，并大大降低LSC的白血病启动能力，从而提供消除CML患者LSC的新策略。如使用CML小鼠模型所示，其中在EC和/或LSC中有条件地敲除了Mir126a（编码miR-126）。TKI处理对BCR-ABL的抑制作用导致内源性miR-126水平异常增加，从而增强了LSC的静止性和持久性。LSC和/或EC中的Mir126a敲除，或用靶向LSC和EC中miR-126表达的miR-126抑制剂治疗，可增强TKI治疗的体内抗白血病作用，并大大降低LSC的白血病启动能力，从而提供消除CML患者LSC的新策略。