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Immunology

Constitutive IRF8 expression inhibits AML by activation of repressed immune response signaling

Leukemia volume 29, pages 157–168 (2015)Cite this article

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Abstract

Myeloid differentiation is blocked in acute myeloid leukemia (AML), but the molecular mechanisms are not well characterized. Meningioma 1 (MN1) is overexpressed in AML patients and confers resistance to all-trans retinoic acid-induced differentiation. To understand the role of MN1 as a transcriptional regulator in myeloid differentiation, we fused transcriptional activation (VP16) or repression (M33) domains with MN1 and characterized these cells in vivo. Transcriptional activation of MN1 target genes induced myeloproliferative disease with long latency and differentiation potential to mature neutrophils. A large proportion of differentially expressed genes between leukemic MN1 and differentiation-permissive MN1VP16 cells belonged to the immune response pathway like interferon-response factor (Irf) 8 and Ccl9. As MN1 is a cofactor of MEIS1 and retinoic acid receptor alpha (RARA), we compared chromatin occupancy between these genes. Immune response genes that were upregulated in MN1VP16 cells were co-targeted by MN1 and MEIS1, but not RARA, suggesting that myeloid differentiation is blocked through transcriptional repression of shared target genes of MN1 and MEIS1. Constitutive expression of Irf8 or its target gene Ccl9 identified these genes as potent inhibitors of murine and human leukemias in vivo. Our data show that MN1 prevents activation of the immune response pathway, and suggest restoration of IRF8 signaling as therapeutic target in AML.

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Acknowledgements

We thank Dr AM Baru and PD Dr Michael Morgan for discussions and Renate Schottmann and Martin Wichmann for technical help. We also thank Dr Matthias Ballmaier and the staff of the Cell Sorting Core Facility of Hannover Medical School for their excellent service (supported in part by the Braukmann-Wittenberg-Herz-Stiftung). This study was supported by DFG grants HE 5240/5-1, grants DJCLS H09/1f, R 10/22, SP 12/02 and R13/14 from Deutsche-José-Carreras Leukämie-Stiftung e.V., grants 109003, 110284, 110292 and 111267 from Deutsche Krebshilfe and the German Federal Ministry of Education and Research grant 01EO0802 (IFB-Tx).

Author contributions

A Sharma and MH designed the research; A Sharma, HY, NJ, AC, A Schwarzer, EY, CKL, FK, BA, KG and MH performed the research; and A Sharma, HY, NJ, AC, A Schwarzer, EY, CKL, FK, BA, KG, AG, RKH and MH analyzed the data. A Sharma, HY and MH wrote the manuscript. All authors read and agreed to the final version of the manuscript.

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  1. A Sharma and H Yun: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    A Sharma, H Yun, N Jyotsana, A Chaturvedi, K Görlich, A Ganser & M Heuser

  2. Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany

    A Schwarzer

  3. Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

    E Yung, C K Lai & R K Humphries

  4. Department of Internal Medicine III, University Hospital Medical Center, Ulm, Germany

    F Kuchenbauer

  5. Department of Medical Genetics, HSC, University of Calgary, Calgary, Alberta, Canada

    B Argiropoulos

  6. Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    R K Humphries

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  1. A Sharma
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Sharma, A., Yun, H., Jyotsana, N. et al. Constitutive IRF8 expression inhibits AML by activation of repressed immune response signaling. Leukemia 29, 157–168 (2015). https://doi.org/10.1038/leu.2014.162

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