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Acute myeloid leukemia

MicroRNA-708 is a novel regulator of the Hoxa9 program in myeloid cells

Leukemia volume 34, pages 1253–1265 (2020)Cite this article

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Abstract

MicroRNAs (miRNAs) are commonly deregulated in acute myeloid leukemia (AML), affecting critical genes not only through direct targeting, but also through modulation of downstream effectors. Homeobox (Hox) genes balance self-renewal, proliferation, cell death, and differentiation in many tissues and aberrant Hox gene expression can create a predisposition to leukemogenesis in hematopoietic cells. However, possible linkages between the regulatory pathways of Hox genes and miRNAs are not yet fully resolved. We identified miR-708 to be upregulated in Hoxa9/Meis1 AML inducing cell lines as well as in AML patients. We further showed Meis1 directly targeting miR-708 and modulating its expression through epigenetic transcriptional regulation. CRISPR/Cas9 mediated knockout of miR-708 in Hoxa9/Meis1 cells delayed disease onset in vivo, demonstrating for the first time a pro-leukemic contribution of miR-708 in this context. Overexpression of miR-708 however strongly impeded Hoxa9 mediated transformation and homing capacity in vivo through modulation of adhesion factors and induction of myeloid differentiation. Taken together, we reveal miR-708, a putative tumor suppressor miRNA and direct target of Meis1, as a potent antagonist of the Hoxa9 phenotype but an effector of transformation in Hoxa9/Meis1. This unexpected finding highlights the yet unexplored role of miRNAs as indirect regulators of the Hox program during normal and aberrant hematopoiesis.

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Acknowledgements

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). 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 and the Baustein Startförderung Program of the Medical Faculty, Ulm University. LP was supported by grants from the Swedish Cancer Society (CAN2014/525), the Swedish Childhood Cancer Foundation (PR2014-0125), and Västra Götalandsregionen (ALFGBG-431881).

Authorship contributions

ES designed and performed the experiments and wrote the manuscript. NP, CR, LM, LE, CM, KK, EDM, AHM, AL, AA, SG, NS, PKK and SI performed experiments. AS, PX and MK performed experiments and edited the manuscript. RR and SW performed proteomics experiments and analysis. LF provided patient samples, antibodies and edited the manuscript. HD and KD provided patient samples and edited the manuscript. EL and MH provided sequencing resources and bioinformatical support. RKH provided vectors and edited the manuscript. LP provided array analysis and edited the manuscript. AR and F.K. designed the study and wrote the manuscript.

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  1. These authors contributed equally: Florian Kuchenbauer, Arefeh Rouhi

Authors and Affiliations

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

    Edith Schneider, Nicole Pochert, Christoph Ruess, Christina Miller, Kathrin Krowiorz, Sarah Grasedieck, Nadine Sperb, Hartmut Döhner, Konstanze Döhner, Florian Kuchenbauer & Arefeh Rouhi

  2. Terry Fox Laboratory, British Columbia Cancer, Vancouver, BC, Canada

    Liam MacPhee, Leo Escano, Ping Xiang, R. Keith Humphries, Florian Kuchenbauer & Arefeh Rouhi

  3. Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden

    Erik Delsing Malmberg, Pradeep Kumar Kopparapu, Anna Staffas, Meena Kanduri, Linda Fogelstrand & Lars Palmqvist

  4. Canada’s Michael Smith Genome Sciences Centre, British Columbia Cancer, Vancouver, BC, Canada

    Alireza Heravi-Moussavi & Martin Hirst

  5. Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC, Canada

    Alireza Lorzadeh & Martin Hirst

  6. Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Arghavan Ashouri & Erik Larsson

  7. Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Pradeep Kumar Kopparapu

  8. Clinic of Dermatology and Allergic Diseases, University Hospital Ulm, Ulm, Germany

    Sebastian Iben

  9. Core Unit Mass Spectrometry and Proteomics, Ulm University, Ulm, Germany

    Reinhild Rösler & Sebastian Wiese

  10. Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden

    Linda Fogelstrand & Lars Palmqvist

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  1. Edith Schneider
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Correspondence to Florian Kuchenbauer or Arefeh Rouhi.

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Schneider, E., Pochert, N., Ruess, C. et al. MicroRNA-708 is a novel regulator of the Hoxa9 program in myeloid cells. Leukemia 34, 1253–1265 (2020). https://doi.org/10.1038/s41375-019-0651-1

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