白血病干细胞中获得性 miR-142 缺失足以促使慢性髓性白血病进入急变期。

Acquired miR-142 deficit in leukemic stem cells suffices to drive chronic myeloid leukemia into blast crisis.

机构信息

Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA.

Department of Computational and Quantitative Medicine, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA.

出版信息

Nat Commun. 2023 Sep 1;14(1):5325. doi: 10.1038/s41467-023-41167-z.

DOI:10.1038/s41467-023-41167-z

PMID:37658085

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10474062/

Abstract

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 CD34CD38 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-142BCR-ABL) mice, which develop BC and die sooner than miR-142 wt CML (i.e., miR-142BCR-ABL) mice, which instead remain in CP CML. Leukemic stem cells (LSCs) from miR-142BCR-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-142BCR-ABL mice and patient-derived xenografts.

摘要

慢性髓性白血病（CML）从慢性期（CP）向急变期（BC）的转化机制尚未完全阐明。在这里，我们显示来自 BC CML 患者的 CD34CD38 blasts 中的 miR-142 水平低于来自 CP CML 患者的 miR-142 水平，表明 miR-142 缺陷与 BC 的发生有关。因此，我们构建了 miR-142 敲除 CML（即 miR-142BCR-ABL）小鼠，它们发展为 BC 并比 miR-142wt CML（即 miR-142BCR-ABL）小鼠更早死亡，后者仍处于 CP CML 中。来自 miR-142BCR-ABL 小鼠的白血病干细胞（LSCs）在同基因受体内再现了 BC 表型，支持由 miR-142 缺陷导致的 LSC 转化。“批量”和单细胞 RNA-seq 数据、代谢组学分析和功能代谢测定的状态转换和互信息分析，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 模拟寡核苷酸可挽救 miR-142BCR-ABL 小鼠和患者来源的异种移植物中的 BC 表型。