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

Ayesh K. Seneviratne, Mingjing Xu, Juan J.Aristizabal Henao, Val A. Fajardo, Zhenyue Hao, Veronique Voisin, G. Wei Xu, Rose Hurren, S. Kim, Neil MacLean, Xiaoming Wang, Marcela Gronda, Danny Jeyaraju, Yulia Jitkova, Troy Ketela, Michael Mullokandov, David Sharon, Geethu Thomas, Raphaël Chouinard-Watkins, James R. HawleyCaitlin Schafer, Helen Loo Yau, Zaza Khuchua, Ahmed Aman, Rima Al-awar, Atan Gross, Steven M. Claypool, Richard Bazinet, Mathieu Lupien, Steven Chan, Daniel D. De Carvalho, Mark D. Minden, Gary D. Bader, Ken D. Stark, Paul LeBlanc, Aaron D. Schimmer

Research output: Contribution to journalArticle

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. Seneviratne et al. performed a CRISPR screen and identified tafazzin (TAZ) as important for the growth of leukemia cells. The inhibition of TAZ specifically reduced the stemness of leukemia cells by increasing phosphatidylserine levels and activating toll-like receptor signaling.

Original languageEnglish (US)
Pages (from-to)621-636.e16
JournalCell stem cell
Volume24
Issue number4
DOIs
StatePublished - Apr 4 2019

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Keywords

  • acute myeloid leukemia
  • cancer differentiation
  • cardiolipin
  • leukemia initiating cell
  • mitochondria
  • phosphatidylserine
  • phospholipids
  • tafazzin

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

Cite this

Seneviratne, A. K., Xu, M., Henao, J. J. A., Fajardo, V. A., Hao, Z., Voisin, V., Xu, G. W., Hurren, R., Kim, S., MacLean, N., Wang, X., Gronda, M., Jeyaraju, D., Jitkova, Y., Ketela, T., Mullokandov, M., Sharon, D., Thomas, G., Chouinard-Watkins, R., ... Schimmer, A. D. (2019). The Mitochondrial Transacylase, Tafazzin, Regulates for AML Stemness by Modulating Intracellular Levels of Phospholipids. Cell stem cell, 24(4), 621-636.e16. https://doi.org/10.1016/j.stem.2019.02.020