Loss of FBXO11 function establishes a stem cell program in acute myeloid leukemia through dysregulation of the mitochondrial protease LONP1
Mo, A. Y.-C.; Kincross, H.; Wang, X.; Chang, L. Y.-T.; Duns, G.; Kwan, H.; Lau, T.; Docking, T. R.; Tran, J.; Colborne, S.; Cheng, S.-W. G.; Huang, S.; Gharaee, N.; Willie, E.; Jiang, J.; Parker, J.; Bridgers, J.; Wood, D.; Klein Geltink, R.; Morin, G. B.; Karsan, A.
Show abstract
Acute myeloid leukemia (AML) is an aggressive cancer with very poor outcomes. To identify additional drivers of leukemogenesis, we analyzed sequence data from 1,727 unique individual AML patients, which revealed mutations in ubiquitin ligase family genes in 11.2% of adult AML samples with mutual exclusivity. The Skp1/Cul1/Fbox (SCF) E3 ubiquitin ligase complex gene FBXO11 was the most significantly downregulated gene of the SCF complex in AML. FBXO11 catalyzes K63-linked ubiquitination of a novel target, LONP1, which promotes entry into mitochondria, thereby enhancing mitochondrial respiration. Reduced mitochondrial respiration secondary to FBXO11 depletion imparts myeloid-biased stem cell properties in primary CD34+ hematopoietic stem progenitor cells (HSPC). In a human xenograft model, depletion of FBXO11 cooperated with AML1-ETO and mutant KRASG12D to generate serially transplantable AML enriched for primitive cells. Our findings suggest that reduced FBXO11 primes HSPC for myeloid-biased self-renewal through attenuation of LONP1-mediated regulation of mitochondrial respiration.
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