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

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.

Citation

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. Acquired miR-142 deficit in leukemic stem cells suffices to drive chronic myeloid leukemia into blast crisis. Nature communications. 2023 Sep 01;14(1):5325

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PMID: 37658085

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