@article{728b432fa8c14c9db8d39187fbd31b22,
title = "The Mitochondrial Transacylase, Tafazzin, Regulates for AML Stemness by Modulating Intracellular Levels of Phospholipids",
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.",
keywords = "acute myeloid leukemia, cancer differentiation, cardiolipin, leukemia initiating cell, mitochondria, phosphatidylserine, phospholipids, tafazzin",
author = "Seneviratne, {Ayesh K.} and Mingjing Xu and Henao, {Juan J.Aristizabal} and Fajardo, {Val A.} and Zhenyue Hao and Veronique Voisin and Xu, {G. Wei} and Rose Hurren and S. Kim and Neil MacLean and Xiaoming Wang and Marcela Gronda and Danny Jeyaraju and Yulia Jitkova and Troy Ketela and Michael Mullokandov and David Sharon and Geethu Thomas and Rapha{\"e}l Chouinard-Watkins and Hawley, {James R.} and Caitlin Schafer and Yau, {Helen Loo} and Zaza Khuchua and Ahmed Aman and Rima Al-awar and Atan Gross and Claypool, {Steven M.} and Richard Bazinet and Mathieu Lupien and Steven Chan and {De Carvalho}, {Daniel D.} and Minden, {Mark D.} and Bader, {Gary D.} and Stark, {Ken D.} and Paul LeBlanc and Schimmer, {Aaron D.}",
note = "Funding Information: We thank Jill Flewelling (Princess Margaret Cancer Center) for administrative assistance. We also thank The Center of Applied Genomics at Sick Kids for performing RNA sequencing and analysis, as well as the Microscopy Imaging Laboratory for performing electron microscopy. This work was supported by the Canadian Institutes of Health Research, the Ontario Institute of Cancer Research with funding provided by the Ontario Ministry of Research and Innovation, the Princess Margaret Cancer Centre Foundation, the Ministry of Long Term Health and Planning in the Province of Ontario, and the NIH (R01HL108882 and R01GM111548 to S.M.C.). A.D.S. holds the Barbara Baker Chair Leukemia and Related Diseases. A.K.S. holds the Fredrick Banting and Charles Best Canada Graduate Scholarships-Doctoral Award from the Canadian Institute of Health as well as the McLaughlin Award from the University of Toronto. M.X. holds the Princess Margaret Hospital Postdoctoral Fellowship and Lady Tata Foundation Postdoctoral Fellowship. Conception and Design, Collection, and/or Assembly of Data, Data Analysis, Interpretation, Manuscript Writing, A.K.S. and M.X.; Collection and/or Assembly of Data, Data Analysis, and Interpretation, A.D.S.; Conception and Design, Financial Support, Collection and/or Assembly of Data, Data Analysis and Interpretation, Manuscript Writing, Final Approval of the Manuscript, J.J.A.H. V.A.F. Z.H. V.V. G.W.X. R.H. S.K. N.M. X.W. M.G. D.J. Y.J. T.K. M.M. D.S. G.T. R.C.-W. J.R.H. H.L.Y. C.S. Z.K. A.A. R.A. A.G. S.M.C. R.B. M.L. S.C. D.D.D. M.D.M. G.D.B. K.D.S. and P.L. A.D.S. has received honorariums from Novartis, Jazz, and Otsuka Pharmaceuticals and research support from Medivir AB and Takeda. A.D.S. owns stock in Abbvie Pharmaceuticals. Funding Information: We thank Jill Flewelling (Princess Margaret Cancer Center) for administrative assistance. We also thank The Center of Applied Genomics at Sick Kids for performing RNA sequencing and analysis, as well as the Microscopy Imaging Laboratory for performing electron microscopy. This work was supported by the Canadian Institutes of Health Research , the Ontario Institute of Cancer Research with funding provided by the Ontario Ministry of Research and Innovation , the Princess Margaret Cancer Centre Foundation , the Ministry of Long Term Health and Planning in the Province of Ontario , and the NIH ( R01HL108882 and R01GM111548 to S.M.C.). A.D.S. holds the Barbara Baker Chair Leukemia and Related Diseases . A.K.S. holds the Fredrick Banting and Charles Best Canada Graduate Scholarships-Doctoral Award from the Canadian Institute of Health as well as the McLaughlin Award from the University of Toronto . M.X. holds the Princess Margaret Hospital Postdoctoral Fellowship and Lady Tata Foundation Postdoctoral Fellowship . Publisher Copyright: {\textcopyright} 2019",
year = "2019",
month = apr,
day = "4",
doi = "10.1016/j.stem.2019.02.020",
language = "English (US)",
volume = "24",
pages = "621--636.e16",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "4",
}