Gehr Family Center for Leukemia Research, Hematology Malignancies and Stem Cell Transplantation Institute, City of Hope Medical Center, Duarte, California, USA.
Department of Medical Biotechnology, Biotechnology Center of Ho Chi Minh City, Ho Chi Minh City, Vietnam.
Nat Med. 2018 May;24(4):450-462. doi: 10.1038/nm.4499. Epub 2018 Mar 5.
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.
慢性髓系白血病（CML）患者中的白血病干细胞（LSCs）负责启动和维持克隆性造血。尽管酪氨酸激酶抑制剂（TKI）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，我们表明，尽管 microRNA（miRNA）miR-126 支持 CML LSCs 的静止、自我更新和植入能力，但 CML LSCs 中的 miR-126 水平低于健康个体的长期造血干细胞（LT-HSCs）。CML LSCs 中 miR-126 水平的下调是由于 BCR-ABL 对 Sprouty 相关 EVH1 结构域包含蛋白 1（SPRED1）的磷酸化，导致介导 miRNA 成熟的 RAN-exportin-5-RCC1 复合物抑制。BM 中的内皮细胞（ECs）向 CML LSCs 提供 miR-126 以支持静止和白血病生长，这在使用 CML 小鼠模型中得到了证明，其中 Mir126a（编码 miR-126）在 ECs 和/或 LSCs 中条件性敲除。TKI 治疗抑制 BCR-ABL 会导致内源性 miR-126 水平的意外增加，从而增强 LSC 的静止和持久性。LSCs 和/或 ECs 中的 Mir126a 敲除，或使用针对 LSCs 和 ECs 中 miR-126 表达的 miR-126 抑制剂治疗，增强了 TKI 治疗的体内抗白血病作用，并强烈降低了 LSC 白血病起始能力，为消除 CML 患者中的 LSCs 提供了一种新策略。
