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ACUTE MYELOID LEUKEMIA

The proto-oncogenic miR-106a-363 cluster enhances adverse risk acute myeloid leukemia through mitochondrial activation

Leukemia volume 39, pages 1090–1101 (2025)Cite this article

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Abstract

We investigated the clinical and functional role of the miR-106a-363 cluster in adult acute myeloid leukemia (AML). LAML miRNA-Seq TCGA analyses revealed that high expression of miR-106a-363 cluster members was associated with inferior survival, and miR-106a-5p and miR-20b-5p levels were significantly elevated in patients with adverse risk AML. Overexpression of the miR-106a-363 cluster and its individual members in a murine AML model significantly accelerated leukemogenesis. Proteomics analysis of leukemic bone marrow cells from these models emphasized the deregulation of proteins involved in intracellular transport, protein complex organization and mitochondrial function, driven predominantly by miR-106a-5p. These molecular alterations suggested mitochondrial activation as a potential mechanism for the observed increase in leukemogenicity. High-resolution respirometry and STED microscopy confirmed that miR-106a-5p enhances mitochondrial respiratory activity and increases mitochondrial volume. These findings demonstrate that the miR-106a-363 cluster, and particularly miR-106a-5p, contribute to AML progression through modulation of mitochondrial function and deregulation of mitochondria-coordinated pathways.

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Fig. 1: Association of the miR-106a-363 cluster miRNAs with disease outcomes and AML karyotype in the TCGA LAML dataset.
Fig. 2: miRNAs in the miR-106a-363 cluster are enriched in primitive hematopoietic cells, are downregulated during AML remission and exacerbate disease in the mouse model of leukemia.
Fig. 3: Proteomic analysis of the moribund mouse BM indicates diverse roles of individual miRNAs in the miR-106a-363 cluster in AML development.
Fig. 4: miR-106a overexpression leads to changes in mitochondrial structure and function.

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All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

We thank Edith Schneider for providing the Hoxa9/Meis1 cell line; the staff at Sahlgrenska University Hospital, especially Giti Shah Barkhordar, for assistance with biobanked samples; the Flow Core at BCCRC for cell sorting; Leonard Foster and Jason Rogalski at UBC’s Proteomics Core Facility for help with OCIAML3 proteomics; and Keng C. Chou, Department of Chemistry, UBC, for access to the STED microscope.

Funding

FK was supported by grants from Deutsche Krebshilfe grant 109420 (Max-Eder program); fellowship 2010/04 by the European Hematology Association; and by the Deutsche Forschungsgemeinschaft (DFG) (SFB 1074, project A5) and the Wilhelm Sander Stiftung (2015.153.1), Leukemia Lymphoma Society of Canada and Michael Smith Health Research BC. AR was supported by the DFG (SFB 1074, project A5) as well as the gender equality program by the DFG (SFB 1074, project Z2), a fellowship from the Canadian Institutes of Health Research, the Baustein Startförderung Program of the Medical Faculty, Ulm University and Faculty of Medicine New Faculty Research Award. LP was supported by grants from the Swedish Cancer Society (CAN2014/525), the Swedish Childhood Cancer Foundation (PR2014-0125), and Västra Götalandsregionen (ALFGBG-431881). NS, KK and SG were supported by the International Graduate School of Molecular Medicine, Ulm University, Germany. MRG and LA were supported by grants from the Canadian Institutes of Health Research (PJT-166196) and the Natural Sciences and Engineering Research Council of Canada (AWD-010517).

Author information

Author notes

  1. These authors contributed equally: Nadine Sperb, Irina A. Maksakova.

  2. These authors jointly supervised this work: Arefeh Rouhi and Florian Kuchenbauer

Authors and Affiliations

  1. Department of Internal Medicine III, University Hospital Ulm, Ulm, 89081, Germany

    Nadine Sperb, Kathrin Krowiorz, Sarah Grasedieck, Nicole Pochert & Christoph Ruess

  2. Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada

    Irina A. Maksakova, Leo Escano, Liam MacPhee, Ariene Cabantog, Dexter Kim, Mansen Yu, Junbum Im, Arefeh Rouhi & Florian Kuchenbauer

  3. Department. of Microbiology and Immunology and the Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada

    Libin Abraham & Michael R. Gold

  4. Department for Gynecology and Obstetrics, University Hospital Augsburg, Stenglinstrasse 2, 86156, Augsburg, Germany

    Nicole Pochert

  5. Core Unit Mass Spectrometry and Proteomics, Ulm University, Ulm, 89081, Germany

    Reinhild Rösler & Sebastian Wiese

  6. Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada

    Stephane Flibotte

  7. Institute of Experimental Hematology, Hannover Medical School, Hannover, 30625, Germany

    Tobias Maetzig

  8. Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany

    Tobias Maetzig

  9. Institute for Anesthesiological pathophysiology and procedure development, Ulm University Hospital, Helmholtzstrasse 8/1, 89081, Ulm, Germany

    Enrico Calzia

  10. Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, 41345, Sweden

    Lars Palmqvist & Linda Fogelstrand

  11. Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Chemistry, Gothenburg, 41345, Sweden

    Lars Palmqvist & Linda Fogelstrand

  12. Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, Canada

    Arefeh Rouhi & Florian Kuchenbauer

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  1. Nadine Sperb
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Contributions

NS and IAM performed experimental work, analyses, and prepared the manuscript. LE provided bioinformatic analysis. LA and MRG performed imaging. JB, LM, AC, DK, MY, KK, SG, NP, CR, RR, TM and SF provided experimental support. EC performed respirometry support. LP and SW performed proteomics. LF performed FACS and human assays. AR and FK conceived and designed the study and wrote the manuscript.

Corresponding author

Correspondence to Florian Kuchenbauer.

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The authors declare no competing interests.

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All methods were performed in accordance with the relevant guidelines and regulations. Animal experiments with H9M and H9M cells were approved by the state government of Tübingen, Germany. Animal experiments with OCIAML3 cells were performed according to animal research protocol # A19-0320 approved by the University of British Columbia Animal Care and Use Committee. All patients provided informed consent under protocols approved by the Regional Ethical Review Board in Gothenburg.

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Sperb, N., Maksakova, I.A., Escano, L. et al. The proto-oncogenic miR-106a-363 cluster enhances adverse risk acute myeloid leukemia through mitochondrial activation. Leukemia 39, 1090–1101 (2025). https://doi.org/10.1038/s41375-025-02558-x

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