ACSL4-associated lipid metabolism is a distinct therapeutic vulnerability in KMT2A-rearranged acute myeloid leukemia
Year: 2026
Type: article
Abstract: Deregulated lipid metabolism contributes to leukemogenesis and the progression of acute myeloid leukemia (AML). By analyzing large-scale CRISPR-Cas9 screening data, we identified acyl-CoA synthetase long-chain family member 4 (ACSL4) as a selective vulnerability in lysine methyltransferase 2A-rearranged (KMT2Ar) AML. Functional validation using CRISPR interference and short hairpin RNA knockdown confirmed that ACSL4 loss impairs the growth of KMT2Ar but not non-KMT2Ar AML cells. ACSL4 knockdown reduced colony formation in cells derived from patients with KMT2Ar AML and murine MLL-AF9 cells and delayed leukemia onset in vivo in MLL-AF9 mice. A multi-omics approach, including transcriptomics, proteomics, and lipidomics, revealed depletion of polyunsaturated lipid species and compensatory activation of lipid metabolic pathways upon ACSL4 loss. Supplementation with exogenous polyunsaturated fatty acids (PUFAs) rescued the growth defect, linking ACSL4 dependency to defective PUFA utilization. Finally, we generated a KMT2Ar-ACSL4 dependency signature (KRADS12) that correlates with KMT2Ar status and predicts poor survival in patients with AML.
Source: Cell Reports
Authors: Silvia Schäfer, Elahe Rahimian, Lola Schmitz-Hübsch, Mehak Shaikh, Silke Brilloff, Vida Kufrin, Sandra Küchler, Maria Fedorova, Natalie Kusebauch, Zhixu Ni, Dominic Helm, Irmela Jeremias, Denis M. Schewe, Claudia R. Ball, Martin Bornhäuser, Hanno Glimm, Meritxell Alberich-Jorda, Marius Bill, Alexander A. Wurm
Institutions: Helmholtz-Zentrum Dresden-Rossendorf, University Hospital Carl Gustav Carus, Nationales Centrum für Tumorerkrankungen Dresden, Technische Universität Dresden, Charles University, Czech Academy of Sciences, Institute of Molecular Genetics, German Cancer Research Center, LMU Klinikum, Ludwig-Maximilians-Universität München, German Cancer Consortium (DKTK) Dresden, University Hospital in Motol
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: National Cancer Research Institute, European Commission, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Technische Universität Dresden, Deutsche Krebshilfe, Sächsisches Staatsministerium für Wissenschaft und Kunst, Sächsische Aufbaubank, Nationales Centrum für Tumorerkrankungen Heidelberg, Københavns Professionshøjskole
OpenAlex ID: W7130405472