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Disruption of polyunsaturated fatty acid biosynthesis drives STING-dependent acute myeloid leukemia cell maturation and death

Kanefsky, Joice
; 
Basse, Mary
; 
Sokei, Judith
; 
di Martino, Orsola
; 
Valin, Liana
; 
Jaspers, Yorrick
; 
Martinez, Esteban
; 
Huhn, Jacklyn
; 
Di Marcantonio, Daniela
; 
Magee, Jeffrey A.
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Journal article
Date
2024-03-22
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Temple Health (Temple University)
Fox Chase Cancer Center (Temple University)
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Subject
AML
 FADS1
 PUFA
 STING
 Phospholipid
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https://scholarshare.temple.edu/handle/20.500.12613/11878
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DOI
https://doi.org/10.1016/j.jbc.2024.107214
Abstract
The role of polyunsaturated fatty acid (PUFA) biosynthesis in acute myeloid leukemia (AML) remains largely undefined. A comparative expression analysis of 35 genes encoding fatty acid biosynthesis enzymes showed that fatty acid desaturase 1 (FADS1) was highly expressed across multiple AML subtypes relative to healthy controls and that elevated FADS1 expression correlates with worse overall AML patient survival. Functionally, shRNA-mediated inhibition of FADS1 reduced AML cell growth in vitro and significantly delayed leukemia onset in an AML mouse model. AML cell lines depleted of FADS1 arrested in the G1/S-phase of the cell cycle, acquired characteristics of myeloid maturation and subsequently died. To understand the molecular consequences of FADS1 inhibition, a combination of mass spectrometry–based analysis of complex lipids and gene expression analysis (RNA-seq) was performed. FADS1 inhibition caused AML cells to exhibit significant lipidomic remodeling, including depletion of PUFAs from the phospholipids, phosphatidylserine, and phosphatidylethanolamine. These lipidomic alterations were accompanied by an increase induction of inflammatory and stimulator of interferon genes (STING)-mediated type-1 interferon signaling. Remarkably, genetic deletion of STING largely prevented the AML cell maturation and death phenotypes mediated by FADS1 inhibition. Highlighting the therapeutic implications of these findings, pharmacological blockade of PUFA biosynthesis reduced patient-derived AML cell numbers ex vivo but not that of healthy donor cells. Similarly, STING agonism attenuated patient-derived–AML survival; however, STING activation also reduced healthy granulocyte numbers. Collectively, these data unveil a previously unrecognized importance of PUFA biosynthesis in leukemogenesis and that imbalances in PUFA metabolism can drive STING-mediated AML maturation and death.
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Joice Kanefsky, Mary Basse, Judith Sokei, Orsola di Martino, Liana Valin, Yorrick Jaspers, Esteban Martinez, Jacklyn Huhn, Daniela Di Marcantonio, Jeffrey A. Magee, Aaron R. Goldman, Hsin-Yao Tang, Francesca Ferraro, Stephan Kemp, David L. Wiest, Stephen M. Sykes, Disruption of polyunsaturated fatty acid biosynthesis drives STING-dependent acute myeloid leukemia cell maturation and death, Journal of Biological Chemistry, Volume 300, Issue 5, 2024, 107214, ISSN 0021-9258, https://doi.org/10.1016/j.jbc.2024.107214. (https://www.sciencedirect.com/science/article/pii/S0021925824017095)
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American Society for Biochemistry and Molecular Biology Inc.
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The Journal of Biological Chemistry, Vol. 300, Iss. 5
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