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

• Published in: Cell stem cell 2019-04, Vol.24 (4), p.621-636.e16
• Main Authors: Seneviratne, Ayesh K., Xu, Mingjing, Henao, Juan J. Aristizabal, Fajardo, Val A., Hao, Zhenyue, Voisin, Veronique, Xu, G. Wei, Hurren, Rose, Kim, S., MacLean, Neil, Wang, Xiaoming, Gronda, Marcela, Jeyaraju, Danny, Jitkova, Yulia, Ketela, Troy, Mullokandov, Michael, Sharon, David, Thomas, Geethu, Chouinard-Watkins, Raphaël, Hawley, James R., Schafer, Caitlin, Yau, Helen Loo, Khuchua, Zaza, Aman, Ahmed, Al-awar, Rima, Gross, Atan, Claypool, Steven M., Bazinet, Richard P., Lupien, Mathieu, Chan, Steven, De Carvalho, Daniel D., Minden, Mark D., Bader, Gary D., Stark, Ken D., LeBlanc, Paul, Schimmer, Aaron D.
• Format: Article
• Language: English
• Subjects: acute myeloid leukemia; Animals; cancer differentiation; cardiolipin; Cell Line, Tumor; Doxorubicin - pharmacology; Female; Humans; leukemia initiating cell; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Male; Mice; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; mitochondria; Mitochondria - enzymology; phosphatidylserine; phospholipids; Phospholipids - metabolism; Signal Transduction - drug effects; tafazzin; Toll-Like Receptors - metabolism; Transcription Factors - antagonists & inhibitors; Transcription Factors - deficiency; Transcription Factors - metabolism
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2019.02.020

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. [Display omitted] •Inhibiting TAZ leads to increased levels of PS in AML cells•TAZ and PS regulate AML stemness•Reducing TAZ or increasing PS decreases AML stemness and activates TLR signaling•Increasing PS is a potential therapeutic strategy for AML 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.