4.8 Article

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

Journal

NATURE COMMUNICATIONS
Volume 14, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41467-023-41167-z

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The mechanisms underlying the transformation of chronic phase (CP) to blast crisis (BC) in chronic myeloid leukemia (CML) are not fully understood. This study reveals that deficiency of miR-142 drives the progression of CML to BC by regulating mitochondrial metabolism, and it may serve as a potential therapeutic target to prevent BC in CML.
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 & beta;-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.

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