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

Nadine Sperb^#¹, Irina A Maksakova^#², Leo Escano², Libin Abraham³, Liam MacPhee², Ariene Cabantog², Dexter Kim², Mansen Yu², Kathrin Krowiorz¹, Junbum Im², Sarah Grasedieck¹, Nicole Pochert^{1

4}, Christoph Ruess¹, Reinhild Rösler⁵, Stephane Flibotte⁶, Tobias Maetzig^{7

8}, Enrico Calzia⁹, Lars Palmqvist^{10

11}, Sebastian Wiese⁵, Linda Fogelstrand^{10

11}, Michael R Gold³, Arefeh Rouhi^{2

12}, Florian Kuchenbauer^{13

14}

Affiliations

¹ Department of Internal Medicine III, University Hospital Ulm, Ulm, 89081, Germany.
² Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.
³ Department. of Microbiology and Immunology and the Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
⁴ Department for Gynecology and Obstetrics, University Hospital Augsburg, Stenglinstrasse 2, 86156, Augsburg, Germany.
⁵ Core Unit Mass Spectrometry and Proteomics, Ulm University, Ulm, 89081, Germany.
⁶ Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
⁷ Institute of Experimental Hematology, Hannover Medical School, Hannover, 30625, Germany.
⁸ Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
⁹ Institute for Anesthesiological pathophysiology and procedure development, Ulm University Hospital, Helmholtzstrasse 8/1, 89081, Ulm, Germany.
¹⁰ Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, 41345, Sweden.
¹¹ Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Chemistry, Gothenburg, 41345, Sweden.
¹² Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, Canada.
¹³ Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. fkuchenbauer@bccrc.ca.
¹⁴ Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, Canada. fkuchenbauer@bccrc.ca.

^# Contributed equally.

PMID: 40097604
DOI: 10.1038/s41375-025-02558-x

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

Nadine Sperb et al. Leukemia. 2025 May.

. 2025 May;39(5):1090-1101.

doi: 10.1038/s41375-025-02558-x. Epub 2025 Mar 17.

Authors

Affiliations

¹ Department of Internal Medicine III, University Hospital Ulm, Ulm, 89081, Germany.
² Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.
³ Department. of Microbiology and Immunology and the Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
⁴ Department for Gynecology and Obstetrics, University Hospital Augsburg, Stenglinstrasse 2, 86156, Augsburg, Germany.
⁵ Core Unit Mass Spectrometry and Proteomics, Ulm University, Ulm, 89081, Germany.
⁶ Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
⁷ Institute of Experimental Hematology, Hannover Medical School, Hannover, 30625, Germany.
⁸ Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
⁹ Institute for Anesthesiological pathophysiology and procedure development, Ulm University Hospital, Helmholtzstrasse 8/1, 89081, Ulm, Germany.
¹⁰ Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, 41345, Sweden.
¹¹ Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Chemistry, Gothenburg, 41345, Sweden.
¹² Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, Canada.
¹³ Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. fkuchenbauer@bccrc.ca.
¹⁴ Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, Canada. fkuchenbauer@bccrc.ca.

^# Contributed equally.

PMID: 40097604
DOI: 10.1038/s41375-025-02558-x

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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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: 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.

References

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

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

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