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000309982 1001_ $$aSchäfer, Silvia$$b0
000309982 245__ $$aACSL4-associated lipid metabolism is a distinct therapeutic vulnerability in KMT2A-rearranged acute myeloid leukemia.
000309982 260__ $$aMaryland Heights, MO$$bCell Press$$c2026
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000309982 520__ $$aDeregulated lipid metabolism contributes to leukemogenesis and the progression of acute myeloid leukemia (AML). By analyzing large-scale CRISPR-Cas9 screening data, we identified acyl-CoA synthetase long-chain family member 4 (ACSL4) as a selective vulnerability in lysine methyltransferase 2A-rearranged (KMT2Ar) AML. Functional validation using CRISPR interference and short hairpin RNA knockdown confirmed that ACSL4 loss impairs the growth of KMT2Ar but not non-KMT2Ar AML cells. ACSL4 knockdown reduced colony formation in cells derived from patients with KMT2Ar AML and murine MLL-AF9 cells and delayed leukemia onset in vivo in MLL-AF9 mice. A multi-omics approach, including transcriptomics, proteomics, and lipidomics, revealed depletion of polyunsaturated lipid species and compensatory activation of lipid metabolic pathways upon ACSL4 loss. Supplementation with exogenous polyunsaturated fatty acids (PUFAs) rescued the growth defect, linking ACSL4 dependency to defective PUFA utilization. Finally, we generated a KMT2Ar-ACSL4 dependency signature (KRADS12) that correlates with KMT2Ar status and predicts poor survival in patients with AML.
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000309982 650_7 $$2Other$$aCP: cancer
000309982 650_7 $$2Other$$aCP: metabolism
000309982 650_7 $$2Other$$aacute myeloid leukemia
000309982 650_7 $$2Other$$achromosomal rearrangements
000309982 650_7 $$2Other$$alipid metabolism
000309982 7001_ $$aRahimian, Elahe$$b1
000309982 7001_ $$aSchmitz-Hübsch, Lola$$b2
000309982 7001_ $$aShaikh, Mehak$$b3
000309982 7001_ $$aBrilloff, Silke$$b4
000309982 7001_ $$aKufrin, Vida$$b5
000309982 7001_ $$aKüchler, Sandra$$b6
000309982 7001_ $$aFedorova, Maria$$b7
000309982 7001_ $$aKusebauch, Natalie$$b8
000309982 7001_ $$aNi, Zhixu$$b9
000309982 7001_ $$0P:(DE-He78)daaed5a5b968028e6e95d273150d5ab1$$aHelm, Dominic$$b10$$udkfz
000309982 7001_ $$aJeremias, Irmela$$b11
000309982 7001_ $$aSchewe, Denis M$$b12
000309982 7001_ $$aBall, Claudia R$$b13
000309982 7001_ $$aBornhäuser, Martin$$b14
000309982 7001_ $$0P:(DE-He78)157277fe62f07df1732f9d126a51d1b9$$aGlimm, Hanno$$b15
000309982 7001_ $$aAlberich-Jorda, Meritxell$$b16
000309982 7001_ $$0P:(DE-He78)3e8aacf45abb87d22071314b72805dc6$$aBill, Marius$$b17
000309982 7001_ $$0P:(DE-He78)cc78445a2cc45a9edf8ee2160a1adbb4$$aWurm, Alexander Arthur$$b18
000309982 773__ $$0PERI:(DE-600)2649101-1$$a10.1016/j.celrep.2026.117010$$gVol. 45, no. 3, p. 117010 -$$n3$$p117010$$tCell reports$$v45$$x2211-1247$$y2026
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