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Leukemia. 2014 May 20. doi: 10.1038/leu.2014.162. [Epub ahead of print]

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

Author information

  • 1Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
  • 2Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
  • 3Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
  • 4Department of Internal Medicine III, University Hospital Medical Center, Ulm, Germany.
  • 5Department of Medical Genetics, HSC, University of Calgary, Calgary, Alberta, Canada.
  • 61] Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada [2] Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

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.Leukemia advance online publication, 24 June 2014; doi:10.1038/leu.2014.162.

PMID:
24957708
[PubMed - as supplied by publisher]
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