Mitochondrial carrier homolog 2 is necessary for AML survival

Blood. 2020 Jul 2;136(1):81-92. doi: 10.1182/blood.2019000106.

Abstract

Through a clustered regularly insterspaced short palindromic repeats (CRISPR) screen to identify mitochondrial genes necessary for the growth of acute myeloid leukemia (AML) cells, we identified the mitochondrial outer membrane protein mitochondrial carrier homolog 2 (MTCH2). In AML, knockdown of MTCH2 decreased growth, reduced engraftment potential of stem cells, and induced differentiation. Inhibiting MTCH2 in AML cells increased nuclear pyruvate and pyruvate dehydrogenase (PDH), which induced histone acetylation and subsequently promoted the differentiation of AML cells. Thus, we have defined a new mechanism by which mitochondria and metabolism regulate AML stem cells and gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • CRISPR-Cas Systems
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Fetal Blood / cytology
  • Gene Expression Regulation, Leukemic / genetics
  • Gene Knockdown Techniques
  • Histones / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism*
  • Mitochondrial Membrane Transport Proteins / physiology*
  • Myeloid-Lymphoid Leukemia Protein / physiology
  • Neoplasm Proteins / physiology*
  • Oncogene Proteins, Fusion / physiology
  • Protein Processing, Post-Translational
  • Pyruvic Acid / metabolism
  • RNA Interference
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology

Substances

  • Histones
  • MLL-AF9 fusion protein, human
  • MTCH2 protein, human
  • Mitochondrial Membrane Transport Proteins
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • RNA, Small Interfering
  • Myeloid-Lymphoid Leukemia Protein
  • Pyruvic Acid

Grants and funding