biostudies-literatureZhang LStand Up To CancerNational Institutes of Health GrantsThe Margaret E Early Medical Research TrustAlex's Lemonade Stand Foundation for Childhood CancerAlex's Lemonade Stand Foundation for Childhood CancerNCI NIH HHSAmerican Society of HematologyLeukemia Research Foundatione2404620https://www.ebi.ac.uk/biostudies/studies/S-EPMC11809339biostudies-literatureUnknown12(6)Cell signaling pathways are enriched for biological processes crucial for cellular communication, response to external stimuli, and metabolism. Here, a cell signaling-focused CRISPR screen identified cytochrome c oxidase subunit 4 isoform 1 (COX4I1) as a novel vulnerability in acute myeloid leukemia (AML). Depletion of COX4I1 hindered leukemia cell proliferation and impacted in vivo AML progression. Mechanistically, loss of COX4I1 induced mitochondrial stress and ferroptosis, disrupting mitochondrial ultrastructure and oxidative phosphorylation. CRISPR gene tiling scans, coupled with mitochondrial proteomics, dissected critical regions within COX4I1 essential for leukemia cell survival, providing detailed insights into the mitochondrial Complex IV assembly network. Furthermore, COX4I1 deplAdvanced science (Weinheim, Baden-Wurttemberg, Germany)Nuclear Control of Mitochondrial Homeostasis and Venetoclax Efficacy in AML via COX4I1.PMC11809339CA233691CA285114R37 CA292678CA280389R01 CA236626R01 CA280389U54 CA243124CA24338618‐11849CA233922CA197489R01 CA278050U54 CA285116CA278050R01 CA243386P30 CA033572R01 CA271497R01 CA214965R01 CA236399CA243124R37 CA233691CA033572CA271497RT617ASH Scholar Junior FacultyR01 CA233922R01 CA211614CA292678CA23662618-11849R01 CA296394U54 CA285114Elsayed ZWang TYPokharel SPYang LChen JZhang HChen CDLiu QZhang LChan AKNChou TFMattson NMLi MRosen STKang HSu RFoong LCKuang BSingh PWang XfalseNuclear Control of Mitochondrial Homeostasis and Venetoclax Efficacy in AML via COX4I1.Cell signaling pathways are enriched for biological processes crucial for cellular communication, response to external stimuli, and metabolism. Here, a cell signaling-focused CRISPR screen identified cytochrome c oxidase subunit 4 isoform 1 (COX4I1) as a novel vulnerability in acute myeloid leukemia (AML). Depletion of COX4I1 hindered leukemia cell proliferation and impacted in vivo AML progression. Mechanistically, loss of COX4I1 induced mitochondrial stress and ferroptosis, disrupting mitochondrial ultrastructure and oxidative phosphorylation. CRISPR gene tiling scans, coupled with mitochondrial proteomics, dissected critical regions within COX4I1 essential for leukemia cell survival, providing detailed insights into the mitochondrial Complex IV assembly network. Furthermore, COX4I1 depl2025-01-01T00:00:00Z2025 Feb2026-05-02T14:33:40.729Z2025-04-07T07:50:05.218ZS-EPMC118093393971685610.1002/advs.202404620