Mir142 loss unlocks IDH2 R140-dependent leukemogenesis through antagonistic regulation of HOX genes

Sci Rep. 2020 Nov 10;10(1):19390. doi: 10.1038/s41598-020-76218-8.

Abstract

AML is a genetically heterogeneous disease and understanding how different co-occurring mutations cooperate to drive leukemogenesis will be crucial for improving diagnostic and therapeutic options for patients. MIR142 mutations have been recurrently detected in IDH-mutated AML samples. Here, we have used a mouse model to investigate the interaction between these two mutations and demonstrate a striking synergy between Mir142 loss-of-function and IDH2R140Q, with only recipients of double mutant cells succumbing to leukemia. Transcriptomic analysis of the non-leukemic single and leukemic double mutant progenitors, isolated from these mice, suggested a novel mechanism of cooperation whereby Mir142 loss-of-function counteracts aberrant silencing of Hoxa cluster genes by IDH2R140Q. Our analysis suggests that IDH2R140Q is an incoherent oncogene, with both positive and negative impacts on leukemogenesis, which requires the action of cooperating mutations to alleviate repression of Hoxa genes in order to advance to leukemia. This model, therefore, provides a compelling rationale for understanding how different mutations cooperate to drive leukemogenesis and the context-dependent effects of oncogenic mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Leukemic / genetics
  • Gene Expression Regulation, Leukemic / physiology*
  • Genotype
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / metabolism*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology*
  • Male
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Mutation / genetics

Substances

  • Homeodomain Proteins
  • MicroRNAs
  • Mirn142 microRNA, mouse
  • Isocitrate Dehydrogenase