title: Constitutive IRF8 expression inhibits AML by activation of repressed immune response signaling.
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.
authors: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors: A
authors: A
authors: Sharma
authors: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors: H
authors: H
authors: Yun
authors: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors: N
authors: N
authors: Jyotsana
authors: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors: A
authors: A
authors: Chaturvedi
authors: Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
authors: A
authors: A
authors: Schwarzer
authors: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors: E
authors: E
authors: Yung
authors: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors: C K
authors: CK
authors: Lai
authors: Department of Internal Medicine III, University Hospital Medical Center, Ulm, Germany.
authors: F
authors: F
authors: Kuchenbauer
authors: Department of Medical Genetics, HSC, University of Calgary, Calgary, Alberta, Canada.
authors: B
authors: B
authors: Argiropoulos
authors: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors: K
authors: K
authors: Görlich
authors: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors: A
authors: A
authors: Ganser
authors: 1] Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada [2] Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors: R K
authors: RK
authors: Humphries
authors: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors: M
authors: M
authors: Heuser
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015534:Trans-Activators; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8
chemical_list: D050835:Interferon Regulatory Factors; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D000099185:Interferon Regulatory Factor-8; C506524:MN1 protein, human