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

• Published in: Nature communications Vol. 14; no. 1; pp. 5325 - 21
• Main Authors: Zhang, Bin, Zhao, Dandan, Chen, Fang, Frankhouser, David, Wang, Huafeng, Pathak, Khyatiben V., Dong, Lei, Torres, Anakaren, Garcia-Mansfield, Krystine, Zhang, Yi, Hoang, Dinh Hoa, Chen, Min-Hsuan, Tao, Shu, Cho, Hyejin, Liang, Yong, Perrotti, Danilo, Branciamore, Sergio, Rockne, Russell, Wu, Xiwei, Ghoda, Lucy, Li, Ling, Jin, Jie, Chen, Jianjun, Yu, Jianhua, Caligiuri, Michael A., Kuo, Ya-Huei, Boldin, Mark, Su, Rui, Swiderski, Piotr, Kortylewski, Marcin, Pirrotte, Patrick, Nguyen, Le Xuan Truong, Marcucci, Guido
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-09-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 13/109; 13/31; 14/19; 14/28; 38/1; 38/15; 38/23; 38/77; 38/88; 38/89; 38/91; 631/67/2327; 692/4028/67/1990/283/1896; 692/4028/67/71; Abl protein; Animal models; Animals; BCR protein; Blast Crisis; CD34 antigen; CD38 antigen; Chronic myeloid leukemia; Crises; Evolution; Fatty acids; Fusion protein; Genetic transformation; Humanities and Social Sciences; Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Leukemia, Myeloid, Chronic-Phase; Metabolomics; Mice; MicroRNAs; Molecular modelling; multidisciplinary; Myeloid leukemia; Oxidation; Oxidative phosphorylation; Phenotypes; Phosphorylation; Science; Science (multidisciplinary); Stem Cells; Therapeutic targets; Transformations; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-41167-z

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.
The molecular mechanisms underlying the transformation of Chronic Myeloid Leukaemia (CML) from chronic phase (CP) to blast crisis (BC) are not completely elucidated. Here, the authors show that acquired miR-142 deficiency drives CML BC by regulating mitochondrial metabolism and is a potential therapeutic target to prevent BC in CML murine models.