TY  - JOUR
AU  - Schäfer, Silvia
AU  - Rahimian, Elahe
AU  - Schmitz-Hübsch, Lola
AU  - Shaikh, Mehak
AU  - Brilloff, Silke
AU  - Kufrin, Vida
AU  - Küchler, Sandra
AU  - Fedorova, Maria
AU  - Kusebauch, Natalie
AU  - Ni, Zhixu
AU  - Helm, Dominic
AU  - Jeremias, Irmela
AU  - Schewe, Denis M
AU  - Ball, Claudia R
AU  - Bornhäuser, Martin
AU  - Glimm, Hanno
AU  - Alberich-Jorda, Meritxell
AU  - Bill, Marius
AU  - Wurm, Alexander Arthur
TI  - ACSL4-associated lipid metabolism is a distinct therapeutic vulnerability in KMT2A-rearranged acute myeloid leukemia.
JO  - Cell reports
VL  - 45
IS  - 3
SN  - 2211-1247
CY  - Maryland Heights, MO
PB  - Cell Press
M1  - DKFZ-2026-00408
SP  - 117010
PY  - 2026
AB  - 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.
KW  - CP: cancer (Other)
KW  - CP: metabolism (Other)
KW  - acute myeloid leukemia (Other)
KW  - chromosomal rearrangements (Other)
KW  - lipid metabolism (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:41712378
DO  - DOI:10.1016/j.celrep.2026.117010
UR  - https://inrepo02.dkfz.de/record/309982
ER  -