Acquired miR-142 deficit in leukemic stem cells suffices to drive chronic myeloid leukemia into blast crisis
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Published:2023-09-01
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Zhang BinORCID, Zhao Dandan, Chen Fang, Frankhouser DavidORCID, Wang Huafeng, Pathak Khyatiben V., Dong Lei, Torres Anakaren, Garcia-Mansfield KrystineORCID, Zhang Yi, Hoang Dinh Hoa, Chen Min-Hsuan, Tao ShuORCID, Cho HyejinORCID, Liang YongORCID, Perrotti Danilo, Branciamore Sergio, Rockne RussellORCID, Wu Xiwei, Ghoda Lucy, Li LingORCID, Jin Jie, Chen JianjunORCID, Yu JianhuaORCID, Caligiuri Michael A.ORCID, Kuo Ya-HueiORCID, Boldin Mark, Su RuiORCID, Swiderski Piotr, Kortylewski MarcinORCID, Pirrotte PatrickORCID, Nguyen Le Xuan Truong, Marcucci GuidoORCID
Abstract
AbstractThe 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.
Funder
U.S. Department of Health & Human Services | NIH | National Cancer Institute
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference74 articles.
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