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 3

Depletion of FBXO11 promotes the maintenance of HSPCs with myeloid bias.

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Depletion of FBXO11 promotes the maintenance of HSPCs with myeloid bias....
(A) Heatmap arranged according to pairwise clustering based on the 25 most upregulated and 25 most downregulated genes in FBXO11-depleted cells compared with control in 3 CD34+ HSPC pools from independent participants expressing a nontargeting control shRNA (shCTR) or targeting FBXO11 (shFBXO11#9 and #10). At the bottom of the heatmap, the independent HSPC pool and experimental condition are labeled. (B) GSEA plots in CD34+ HSPC comparing FBXO11 depletion (shFBXO11#9 and #10) to shCTR. Normalized enrichment score (NES) and false discovery rate (FDR) are indicated. All pathways passing FDR < 0.25 are recorded in Supplemental Table 4. (C) Shown are percentages and (D) absolute cell counts of CD34+ HSPCs expressing shCTR or shFBXO11 at day 7 of culture (N = 4). (E) Cell cycle state of CD34+ HSPC was measured by Ki-67/DAPI staining (N = 3 (shCTR), N = 5 (shFBXO11)). (F) Percentages of CD45RA– (corresponding to cultured HSC immunophenotype) and CD45RA+90– (corresponding to cultured hematopoietic progenitor immunophenotype) cells within the CD34+ population are shown (N = 4). (G) Shown are percentages of megakaryocytic (CD41+ CD61+), erythroid (CD71+ CD235a+), and myeloid (CD15+) cells in CD34+ HSPCs expressing shCTR or shFBXO11 after 14 days of culture. (H) Primary CFC from CD34+ HSPC expressing shCTR or shFBXO11 were counted 12 days after plating (N = 5).). P values represent 2-way ANOVAs with Tukey’s test. (I) Colony counts following secondary plating of 50,000 cells from the primary CFC assay shown in panel H (N = 5). All other P values represent 2-tailed t test, error bars represent SD.