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

• Published in: Leukemia Vol. 29; no. 1; pp. 157 - 168
• Main Authors: Sharma, A, Yun, H, Jyotsana, N, Chaturvedi, A, Schwarzer, A, Yung, E, Lai, C K, Kuchenbauer, F, Argiropoulos, B, Görlich, K, Ganser, A, Humphries, R K, Heuser, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-01-2015; Nature Publishing Group
• Subjects: 13; 13/109; 13/31; 13/44; 38; 38/90; 631/250/262; 631/67; 631/67/1990/283/1897; 631/80/86; Acid resistance; Acute myeloid leukemia; Cancer Research; Cell activation; Cell Differentiation; Cell Line, Tumor; Cellular signal transduction; Chromatin; Critical Care Medicine; Differentiation; Domains; Gene expression; Gene silencing; Genes; Genetic aspects; Health aspects; Hematology; Humans; Immune response; Immune system; Intensive; Interferon; Interferon Regulatory Factors - metabolism; Internal Medicine; Latency; Leukemia; Leukemia, Myeloid, Acute - immunology; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - prevention & control; Leukocytes (neutrophilic); Medicine; Medicine & Public Health; Meningioma; Molecular modelling; Myeloid leukemia; Myeloproliferative diseases; Occupancy; Oncology; original-article; Restoration; Retinoic acid; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Signaling; Target recognition; Therapeutic applications; Transcription activation; Transcription factors; Transcriptional Activation; Tumor Suppressor Proteins - metabolism; VP16 protein; Germany
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2014.162

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.