1. The Mitochondrial Transacylase, Tafazzin, Regulates for AML Stemness by Modulating Intracellular Levels of Phospholipids.
- Author
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Seneviratne AK, Xu M, Henao JJA, Fajardo VA, Hao Z, Voisin V, Xu GW, 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, Hawley JR, Schafer C, Yau HL, Khuchua Z, Aman A, Al-Awar R, Gross A, Claypool SM, Bazinet RP, Lupien M, Chan S, De Carvalho DD, Minden MD, Bader GD, Stark KD, LeBlanc P, and Schimmer AD
- Subjects
- Acyltransferases, Animals, Cell Line, Tumor, Doxorubicin pharmacology, Female, Humans, Leukemia, Myeloid, Acute pathology, Male, Mice, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Signal Transduction drug effects, Toll-Like Receptors metabolism, Transcription Factors antagonists & inhibitors, Transcription Factors deficiency, Leukemia, Myeloid, Acute metabolism, Mitochondria enzymology, Phospholipids metabolism, Transcription Factors metabolism
- 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., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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