获得性米R-142在白血病干细胞中的缺失足以将慢性髓性白血病推进为爆发期。
Acquired miR-142 deficit in leukemic stem cells suffices to drive chronic myeloid leukemia into blast crisis.
发表日期：2023 Sep 01
作者：
Bin Zhang, Dandan Zhao, Fang Chen, David Frankhouser, Huafeng Wang, Khyatiben V Pathak, Lei Dong, Anakaren Torres, Krystine Garcia-Mansfield, Yi Zhang, Dinh Hoa Hoang, Min-Hsuan Chen, Shu Tao, Hyejin Cho, Yong Liang, Danilo Perrotti, Sergio Branciamore, Russell Rockne, Xiwei Wu, Lucy Ghoda, Ling Li, Jie Jin, Jianjun Chen, Jianhua Yu, Michael A Caligiuri, Ya-Huei Kuo, Mark Boldin, Rui Su, Piotr Swiderski, Marcin Kortylewski, Patrick Pirrotte, Le Xuan Truong Nguyen, Guido Marcucci
来源：
Stem Cell Research & Therapy
摘要：
慢性骨髓性白血病（CML）从慢性期（CP）向爆发期（BC）发展的机制尚未完全阐明。在这里，我们展示了BC CML患者中CD34+CD38-爆炸细胞中miR-142水平较CP CML患者中低，表明miR-142缺陷与BC进化有关。因此，我们创建了miR-142缺陷的CML（即miR-142-/-BCR-ABL）小鼠，这些小鼠比miR-142 wt CML（即miR-142+/+BCR-ABL）小鼠更早地发展为BC并且死亡，而miR-142 wt CML小鼠仅保持CP CML状态。来自miR-142-/-BCR-ABL小鼠的白血病干细胞（LSCs）在同种移植体中重现了BC表型，支持miR-142缺陷导致LSC转化。通过“群体”和单细胞RNA测序数据的状态转换和互信息分析，代谢组学分析以及功能代谢测定，我们确定了LSCs中增强的脂肪酸β-氧化、氧化磷酸化和线粒体融合是miR-142驱动的BC进化的关键步骤。一种合成的CpG-miR-142模拟寡核苷酸能够挽救miR-142-/-BCR-ABL小鼠和患者来源的异种移植物中的BC表型。© 2023. Springer Nature Limited.
The mechanisms underlying the transformation of chronic myeloid leukemia (CML) from chronic phase (CP) to blast crisis (BC) are not fully elucidated. Here, we show lower levels of miR-142 in CD34+CD38- blasts from BC CML patients than in those from CP CML patients, suggesting that miR-142 deficit is implicated in BC evolution. Thus, we create miR-142 knockout CML (i.e., miR-142-/-BCR-ABL) mice, which develop BC and die sooner than miR-142 wt CML (i.e., miR-142+/+BCR-ABL) mice, which instead remain in CP CML. Leukemic stem cells (LSCs) from miR-142-/-BCR-ABL mice recapitulate the BC phenotype in congenic recipients, supporting LSC transformation by miR-142 deficit. State-transition and mutual information analyses of "bulk" and single cell RNA-seq data, metabolomic profiling and functional metabolic assays identify enhanced fatty acid β-oxidation, oxidative phosphorylation and mitochondrial fusion in LSCs as key steps in miR-142-driven BC evolution. A synthetic CpG-miR-142 mimic oligodeoxynucleotide rescues the BC phenotype in miR-142-/-BCR-ABL mice and patient-derived xenografts.© 2023. Springer Nature Limited.