Inhibition of heme biosynthesis triggers cuproptosis in acute myeloid leukemia

Lewis, AC; Gruber, E; Franich, R; Armstrong, J; Kelly, MJ; Opazo, CM; Low, YC; Flippe, L; Wijanarko, K; Rowe, CL; Mawal, CH; Birrell, A; So, J; Vaidyanathan, S; Ting, K; Semcesen, LN; Last, K; Ang, CS; Pomilio, G; Brown, FC; Wei, AH; Powell, JA; Ng, ES; Frazier, AE; McArthur, K; Lalaoui, N; Stroud, DA; Brown, KK; Johnstone, RW; Kats, LM

Author(s): Lewis, AC; Gruber, E; Franich, R; Armstrong, J; Kelly, MJ; Opazo, CM; Low, YC; Flippe, L; Wijanarko, K; Rowe, CL; Mawal, CH; Birrell, A; So, J; Vaidyanathan, S; Ting, K; Semcesen, LN; Last, K; Ang, CS; Pomilio, G; Brown, FC; Wei, AH; Powell, JA; Ng, ES; Frazier, AE; McArthur, K; Lalaoui, N; Stroud, DA; Brown, KK; Johnstone, RW; Kats, LM;
Details: Publication Year 2026-01-08,Volume 189,Issue #1,Page 215-232
Journal Title: Cell
Publication Type: Research article
Abstract: The ubiquitous metabolite heme has diverse enzymatic and signaling functions in most mammalian cells. Through integrated analyses of mouse models, human cell lines, and primary patient samples, we identify de novo heme biosynthesis as a selective dependency in acute myeloid leukemia (AML). The dependency is underpinned by a propensity of AML cells, and especially leukemic stem cells (LSCs), to downregulate heme biosynthesis enzymes (HBEs), which promotes their self-renewal. Inhibition of HBEs causes the collapse of mitochondrial Complex IV and dysregulates the copper-chaperone system, inducing cuproptosis, a form of programmed cell death brought about by the oligomerization of lipoylated proteins by copper. Moreover, we identify pathways that are synthetic lethal with heme biosynthesis, including glycolysis, which can be leveraged for combination strategies. Altogether, our work uncovers a heme rheostat that is connected to gene expression and drug sensitivity in AML and implicates HBE inhibition as a trigger of cuproptosis.
Publisher: Cell Press
Keywords: *Heme/biosynthesis; *Leukemia, Myeloid, Acute/metabolism/pathology; Humans; Animals; Mice; *Copper/metabolism; Cell Line, Tumor; Neoplastic Stem Cells/metabolism/pathology; Apoptosis; Mitochondria/metabolism; acute myeloid leukemia; cuproptosis; heme biosynthesis; metabolic vulnerability; metabolism; mitochondrial Complex IV
Department(s): Laboratory Research; Haematology
Publisher's Version: https://doi.org/10.1016/j.cell.2025.10.028
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-12-05 02:49:45

Last Modified: 2026-01-22 02:13:26