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ResearchIn-Press PreviewHematology Open Access | 10.1172/JCI181943

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

Hayle Kincross,1 Ya-Chi Angela Mo,1 Xuan Wang,1 Linda Chang,1 Gerben Duns,1 Franziska Mey,1 Jihong Jiang,1 Zurui Zhu,1 Naomi Isak,1 Harwood Kwan,1 Tammy T.Y. Lau,1 T. Roderick Docking,1 Pranav Garg,1 Jessica Tran,1 Shane Colborne,1 Se-Wing Grace Cheng,1 Shujun Huang,1 Nadia Gharaee,1 Elijah Willie,1 Jeremy D.K. Parker,1 Joshua Bridgers,1 Davis Wood,2 Ramon I. Klein Geltink,3 Gregg B. Morin,4 and Aly Karsan1

1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, Canada

2Centre for Comparative Medicine, University of British Columbia, Vancouver, Canada

3Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, Canada

4Department of Basic and Translational Research/A, BC Cancer Research Institute, Vancouver, Canada

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Published November 25, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI181943.
Copyright © 2025, Kincross et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 25, 2025 - Version history
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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 AML patients, which revealed mutations in ubiquitin ligase family genes in 11.2% of adult AML samples 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 reduces 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 (HSPC) 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.

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graphical abstract
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  • Version 1 (November 25, 2025): In-Press Preview
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