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 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

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

School of Medicine

Research output: Contribution to journal › Article

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 language	English (US)
Pages (from-to)	621-636.e16
Journal	Cell stem cell
Volume	24
Issue number	4
DOIs	https://doi.org/10.1016/j.stem.2019.02.020
State	Published - 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

The Mitochondrial Transacylase, Tafazzin, Regulates for AML Stemness by Modulating Intracellular Levels of Phospholipids. / 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; Lupien, Mathieu; Chan, Steven; De Carvalho, Daniel D.; Minden, Mark D.; Bader, Gary D.; Stark, Ken D.; LeBlanc, Paul; Schimmer, Aaron D.

In: Cell stem cell, Vol. 24, No. 4, 04.04.2019, p. 621-636.e16.

Research output: Contribution to journal › Article

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, R, Lupien, M, Chan, S, De Carvalho, DD, Minden, MD, Bader, GD, Stark, KD, LeBlanc, P & Schimmer, AD 2019, 'The Mitochondrial Transacylase, Tafazzin, Regulates for AML Stemness by Modulating Intracellular Levels of Phospholipids', Cell stem cell, vol. 24, no. 4, pp. 621-636.e16. https://doi.org/10.1016/j.stem.2019.02.020

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 ; Lupien, Mathieu ; Chan, Steven ; De Carvalho, Daniel D. ; Minden, Mark D. ; Bader, Gary D. ; Stark, Ken D. ; LeBlanc, Paul ; Schimmer, Aaron D. / The Mitochondrial Transacylase, Tafazzin, Regulates for AML Stemness by Modulating Intracellular Levels of Phospholipids. In: Cell stem cell. 2019 ; Vol. 24, No. 4. pp. 621-636.e16.

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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.",

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AU - Seneviratne, Ayesh K.

AU - Xu, Mingjing

AU - Henao, Juan J.Aristizabal

AU - Fajardo, Val A.

AU - Hao, Zhenyue

AU - Voisin, Veronique

AU - Xu, G. Wei

AU - Hurren, Rose

AU - Kim, S.

AU - MacLean, Neil

AU - Wang, Xiaoming

AU - Gronda, Marcela

AU - Jeyaraju, Danny

AU - Jitkova, Yulia

AU - Ketela, Troy

AU - Mullokandov, Michael

AU - Sharon, David

AU - Thomas, Geethu

AU - Chouinard-Watkins, Raphaël

AU - Hawley, James R.

AU - Schafer, Caitlin

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AU - Khuchua, Zaza

AU - Aman, Ahmed

AU - Al-awar, Rima

AU - Gross, Atan

AU - Claypool, Steven M.

AU - Bazinet, Richard

AU - Lupien, Mathieu

AU - Chan, Steven

AU - De Carvalho, Daniel D.

AU - Minden, Mark D.

AU - Bader, Gary D.

AU - Stark, Ken D.

AU - LeBlanc, Paul

AU - Schimmer, Aaron D.

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N2 - 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.

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10.1016/j.stem.2019.02.020