Loss of FBXO11 function establishes a stem cell program in acute myeloid leukemia through dysregulation of mitochondrial LONP1

Abstract

Acute myeloid leukemia (AML) is an aggressive cancer with very poor outcomes. Analysis of sequencing data from 1,627 unique AML patients revealed frequent mutations in ubiquitin ligase family genes. Loss of function of the Skp1/Cul1/Fbox (SCF) E3 ubiquitin ligase complex genes are found in ~8% of AML patients including recurrent mutations in FBXO11. FBXO11 is the most significantly downregulated gene of the SCF complex in AML samples. Depletion of Fbxo11 promotes myeloid-biased stem cell maintenance and cooperates with AML1-ETO and mutant KRAS to generate serially transplantable mouse and human AML in in vivo models. FBXO11 mediates K63-linked polyubiquitination of the LONP1 mitochondrial protease, and loss of FBXO11 impairs LONP1 activity thereby reducing mitochondrial membrane potential, imparting stem cell properties and driving leukemogenesis. Our findings suggest that loss of FBXO11 function primes HSPC for myeloid-biased self-renewal through attenuation of LONP1-mediated regulation of mitochondrial function.

Fatecode enables cell fate regulator prediction using classification-supervised autoencoder perturbation

“… 74 fbxo11 depletion leads to the hematopoietic population with stem cell characteristics Mo et al. 75 hmgn2 facilitates the maintenance of active chromatin states required for stem cell identity in a pluripotent stem cell model Garza-Manero et al. 76 aspm regulates symmetric stem cell division by tuning Cyclin E ubiquitination Capecchi et al.…”