The Mitochondrial Transacylase, Tafazzin, Regulates for AML Stemness by Modulating Intracellular Levels of Phospholipids

Cell Stem Cell. 2019 Apr 4;24(4):621-636.e16. doi: 10.1016/j.stem.2019.02.020. Epub 2019 Mar 28.

Abstract

Tafazzin (TAZ) is a mitochondrial transacylase that remodels the mitochondrial cardiolipin into its mature form. Through a CRISPR screen, we identified TAZ as necessary for the growth and viability of acute myeloid leukemia (AML) cells. Genetic inhibition of TAZ reduced stemness and increased differentiation of AML cells both in vitro and in vivo. In contrast, knockdown of TAZ did not impair normal hematopoiesis under basal conditions. Mechanistically, inhibition of TAZ decreased levels of cardiolipin but also altered global levels of intracellular phospholipids, including phosphatidylserine, which controlled AML stemness and differentiation by modulating toll-like receptor (TLR) signaling.

Keywords: acute myeloid leukemia; cancer differentiation; cardiolipin; leukemia initiating cell; mitochondria; phosphatidylserine; phospholipids; tafazzin.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Doxorubicin / pharmacology
  • Female
  • Humans
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Mitochondria / enzymology*
  • Phospholipids / metabolism*
  • Signal Transduction / drug effects
  • Toll-Like Receptors / metabolism
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / deficiency
  • Transcription Factors / metabolism*

Substances

  • Phospholipids
  • TAZ protein, human
  • Toll-Like Receptors
  • Transcription Factors
  • Doxorubicin