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

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

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 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blast Crisis
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive*
  • Leukemia, Myeloid*
  • Leukemia, Myeloid, Chronic-Phase*
  • Mice
  • MicroRNAs*
  • Stem Cells

Substances

  • MicroRNAs
  • MIRN142 microRNA, human
  • Mirn142 microRNA, mouse