Journal Article

Loss of FBXO11 establishes a stem cell program in acute myeloid leukemia by dysregulating LONP1

Docking, T. Roderick, Kwan, Harwood, Morin, Gregg B., Wood, Davis, Kincross, Hayle, Gharaee, Nadia, Bridgers, Joshua, Isak, Naomi, Willie, Elijah, Karsan, Aly, Jiang, Jihong, Colborne, Shane, Mey, Franziska, Klein Geltink, Ramon I., Mo, Ya-Chi Angela, Tran, Jessica, Duns, Gerben, Wang, Xuan, Chang, Linda, Zhu, Zurui, Parker, Jeremy D.K., Huang, Shujun, Cheng, Se-Wing Grace, Lau, Tammy T.Y., Garg, Pranav

2026

Overview

Acute myeloid leukemia (AML) is an aggressive cancer with very poor outcomes. To identify additional drivers of leukemogenesis, we analyzed sequencing data from 1,727 unique individual patients with AML, which revealed mutations in ubiquitin ligase family genes in 11.2% of samples from adult patients with AML with mutual exclusivity. The SKP1/CUL1/F-box (SCF) E3 ubiquitin ligase complex gene, FBXO11, was the most significantly downregulated gene of the SCF complex in AML. We found that FBXO11 interacts with and catalyzes K63-linked ubiquitination of LONP1 in the cytosol, to promote LONP1 entry into mitochondria. We show that depletion of FBXO11 or LONP1 reduced mitochondrial respiration through impaired LONP1 chaperone activity to assemble electron transport chain Complex IV. Reduced mitochondrial respiration secondary to FBXO11 or LONP1 depletion imparted myeloid-biased stem cell properties in primary CD34+ hematopoietic stem and progenitor cells (HSPCs) in vitro. In a human xenograft model, depletion of FBXO11 cooperated with AML1-ETO and mutant KRASG12D to generate serially transplantable AML. Our findings suggest that reduced FBXO11 cooperates to initiate AML by priming HSPC for myeloid-biased self renewal through attenuation of LONP1-mediated regulation of mitochondrial respiration.

• Publisher: American Society for Clinical Investigation
• Subject: Acute myeloid leukemia / Alcohol Oxidoreductases - genetics / Alcohol Oxidoreductases - metabolism / AML1 protein / Animals / Bone marrow / CD34 antigen / Cell cycle / Cell death / Cell Line, Tumor / Cell self-renewal / Cooperation / Cytosol / Datasets / Electron transport chain / F-Box Proteins - genetics / F-Box Proteins - metabolism / Female / Gene expression / Gene Expression Regulation, Leukemic / Genotype & phenotype / Hematopoietic stem cells / Hemopoiesis / Humans / Leukemia / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - metabolism / Leukemia, Myeloid, Acute - pathology / Leukemogenesis / Male / Mice / Mitochondria / Mitochondria - genetics / Mitochondria - metabolism / Mitochondria - pathology / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / Mutation / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Progenitor cells / Protein-Arginine N-Methyltransferases - genetics / Protein-Arginine N-Methyltransferases - metabolism / Proteins / Respiration / Stem cells / Ubiquitin-protein ligase / Ubiquitination