Loss of FBXO11 establishes a stem cell program in acute myeloid leukemia by dysregulating LONP1
Hayle Kincross, Ya-Chi Angela Mo, Xuan Wang, Linda Chang, Gerben Duns, Franziska Mey, Jihong Jiang, Zurui Zhu, Naomi Isak, Harwood Kwan, Tammy T.Y. Lau, T. Roderick Docking, Pranav Garg, Jessica Tran, Shane Colborne, Se-Wing Grace Cheng, Shujun Huang, Nadia Gharaee, Elijah Willie, Jeremy D.K. Parker, Joshua Bridgers, Davis Wood, Ramon I. Klein Geltink, Gregg B. Morin, Aly Karsan
Hayle Kincross, Ya-Chi Angela Mo, Xuan Wang, Linda Chang, Gerben Duns, Franziska Mey, Jihong Jiang, Zurui Zhu, Naomi Isak, Harwood Kwan, Tammy T.Y. Lau, T. Roderick Docking, Pranav Garg, Jessica Tran, Shane Colborne, Se-Wing Grace Cheng, Shujun Huang, Nadia Gharaee, Elijah Willie, Jeremy D.K. Parker, Joshua Bridgers, Davis Wood, Ramon I. Klein Geltink, Gregg B. Morin, Aly Karsan
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Research Article Hematology

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

Abstract

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.

Authors

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

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Figure 2

Expression of SCF gene FBXO11 is reduced in AML compared with normal HSPCs.

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Expression of SCF gene FBXO11 is reduced in AML compared with normal HSP...
(A) Shown is a volcano plot comparing transcript expression of SCF genes. P values represent Bonferroni-adjusted 2-tailed t tests. The horizontal dotted line represents P = 0.05. Vertical lines represent log2 fold change of |0.25|. (B) Expression levels of FBXO11 transcripts across different AML subtypes and normal HSPC populations from BloodSpot are represented as a box and whisker plot. The median is shown with a horizontal line, with the edges of the box corresponding to the first and third quartiles of the distribution. P values represent 1-way ANOVA with Dunnett’s test. (C) FBXO11 protein abundance in normal CD34+ cord blood cell pools comprising 1–255 participants (N = 4), and AML bone marrow samples (N = 9). Biological sex indicated as female (F) or male (M). Relative FBXO11 protein (fold-change) is indicated normalized to GAPDH expression, and relative to the 25-participant pool. (D) Quantification of FBXO11 protein abundance in AML relative to normal CD34+ HSPC presented in C. P value represents a 2-tailed t test, error bars represent SD.