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 Hawley; Caitlin Schafer; Helen Loo Yau; Zaza Khuchua; Ahmed Aman; Rima Al-Awar; Atan Gross; Steven M Claypool; Richard P Bazinet; Mathieu Lupien; Steven Chan; Daniel D De Carvalho; Mark D Minden; Gary D Bader; Ken D Stark; Paul LeBlanc; Aaron D Schimmer

doi:10.1016/j.stem.2019.02.020

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.

Authors

Ayesh K Seneviratne¹, Mingjing Xu², Juan J Aristizabal Henao³, Val A Fajardo⁴, Zhenyue Hao², Veronique Voisin⁵, G Wei Xu², Rose Hurren², S Kim², Neil MacLean², Xiaoming Wang², Marcela Gronda², Danny Jeyaraju², Yulia Jitkova², Troy Ketela², Michael Mullokandov⁶, David Sharon², Geethu Thomas², Raphaël Chouinard-Watkins⁷, James R Hawley⁸, Caitlin Schafer⁹, Helen Loo Yau⁸, Zaza Khuchua¹⁰, Ahmed Aman¹¹, Rima Al-Awar¹¹, Atan Gross⁶, Steven M Claypool¹², Richard P Bazinet⁷, Mathieu Lupien⁸, Steven Chan⁸, Daniel D De Carvalho⁸, Mark D Minden⁸, Gary D Bader⁵, Ken D Stark³, Paul LeBlanc⁴, Aaron D Schimmer¹³

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
² Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
³ Laboratory of Nutritional Lipidomics, Department of Kinesiology, University of Waterloo, Waterloo, ON, Canada.
⁴ Department of Health Sciences, Faculty of Applied Health Sciences, Brock University, St. Catharines, ON, Canada.
⁵ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁶ Department of Biological Regulation, Weizmann Institute, Rehovot, Israel.
⁷ Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁹ Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
¹⁰ Department of Biochemistry, Sechenov Medical University, Moscow, Russian Federation; Institute of Medical Research Ilia State University, Tbilisi, Georgia.
¹¹ Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, ON, Canada.
¹² Department of Physiology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹³ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. Electronic address: aaron.schimmer@uhn.ca.

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

Acyltransferases
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
Toll-Like Receptors
Transcription Factors
Doxorubicin
Acyltransferases
TAFAZZIN protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding