Very Long Chain Fatty Acid Synthesis is a Targetable Dependency in RAS Pathway Mutant Leukemia
Abstract Oncogenic RAS pathway mutations are associated with therapeutic resistance in acute myeloid leukemia, and identification of therapeutic vulnerabilities has been hindered by a lack of clinically relevant models and tractable ex vivo platforms. We utilize a bone marrow endothelial cell co-culture system to perform CRISPR screens on wild-type hematopoietic cells and isogenic leukemias with and without mutant Nras. We credentialed Elovl1, a very long chain fatty acid elongase, as a dependency in RAS pathway mutant leukemia using genetic and pharmacologic approaches. Metabolic and genetic studies in primary leukemias revealed that the fitness defect from Elovl1 loss reflects a mutant-specific dependency on de novo sphingolipid biosynthesis, specifically sphingomyelin production, as Sgms1 deletion phenocopies Elovl1 loss. Sphingomyelin-mediated generation of lipid rafts, key scaffolds for multiple signaling pathways, is essential to the survival of Nras-mutant AML cells. Our work leverages a new leukemia model to identify a targetable dependency in this treatment-refractory leukemia.
Authors
- Tak W. Mak (ORCID: https://orcid.org/0000-0001-6766-861X)
- Elisa de Stanchina (ORCID: https://orcid.org/0000-0002-3873-315X)
- Justin R. Cross (ORCID: https://orcid.org/0000-0002-6356-057X)
- Rebecca G. Gelfer (ORCID: https://orcid.org/0000-0002-7270-8249)
- B. Bishal Paudel (ORCID: https://orcid.org/0000-0002-5426-7048)
- Ross L. Levine (ORCID: https://orcid.org/0000-0002-7884-1905)
- Shoron Mowla (ORCID: https://orcid.org/0000-0001-7019-1453)
- Su‐Fern Tan (ORCID: https://orcid.org/0000-0002-8301-0823)
- Todd E. Fox (ORCID: https://orcid.org/0000-0001-5170-3951)
- Michael R. Waarts (ORCID: https://orcid.org/0009-0004-2359-7628)
- Mara Monetti (ORCID: https://orcid.org/0009-0006-9778-9010)
- Matthew G. Wereski (ORCID: https://orcid.org/0009-0000-6766-6366)
- Wenbin Xiao (ORCID: https://orcid.org/0000-0001-8586-8500)
- Merve Şahin (ORCID: https://orcid.org/0000-0003-3858-8332)
- Zhuoning Li (ORCID: https://orcid.org/0009-0005-9064-8170)
- Richard P. Koche (ORCID: https://orcid.org/0000-0002-6820-5083)
- Kaitlyn H. Ko (ORCID: https://orcid.org/0000-0001-5154-0232)
- Angélica C. Romero‐Vega (ORCID: https://orcid.org/0000-0001-8260-7110)
- Christopher A. Famulare (ORCID: https://orcid.org/0000-0002-3366-3965)
- David J. Feith (ORCID: https://orcid.org/0000-0003-4981-1691)
- Michelle Saoi (ORCID: https://orcid.org/0000-0001-7678-6239)
- Sheng F. Cai (ORCID: https://orcid.org/0000-0002-2708-887X)
- Iannis Aifantis (ORCID: https://orcid.org/0000-0001-6857-1035)
- Xiaodi Wu (ORCID: https://orcid.org/0000-0003-0886-8640)
- Maria Sirenko (ORCID: https://orcid.org/0000-0001-7816-8071)
- Maya Bagish (ORCID: https://orcid.org/0009-0004-2356-4105)
- Kevin Yanjun Chen (ORCID: https://orcid.org/0000-0002-3851-6016)
- Clementina Strozek
- Madhuri Madavaram (ORCID: https://orcid.org/0009-0000-5012-5088)
- Gabriel San Miguel-Matos (ORCID: https://orcid.org/0009-0005-8772-761X)
- Nathaniel B. Long (ORCID: https://orcid.org/0009-0006-6180-053X)
Institutions
- University Health Network (CA)
- Memorial Sloan Kettering Cancer Center (US)
- NYU Langone Health (US)
- University of Virginia (US)
- New York University (US)
Publication Details
- Journal
- Blood Cancer Discovery
- Published
- 2026-09-30
- DOI
- https://doi.org/10.1158/2643-3230.bcd-26-0274
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00