IRF8 Gene

The IRF8 gene (IRF8 stands for "Interferon Regulatory Factor 8") is a protein-coding gene located on chromosome 16q24.1.

The protein encoded by the IRF8 gene, the interferon consensus sequence-binding protein (ICSBP), is a transcription factor of the interferon (IFN) regulatory factor (IRF) family. Proteins of this family consist of a conserved DNA-binding domain in the N-terminal region and a divergent C-terminal region that serves as a regulatory domain. The IRF family proteins bind to the IFN-stimulated response element (ISRE) and regulate the expression of genes that are stimulated by type I IFN, namely IFN-alpha and IFN-beta. The IRF family proteins also control the expression of IFN-alpha- and IFN-beta-regulated genes induced by viral infection.

Diseases associated with IRF8 include immunodeficiency 32A and immunodeficiency 32B.

AML: The transcription factor IRF8 has been identified as an AML-specific susceptibility gene in humans. IRF8 is upregulated in a subset of AML cells. Thus, high IRF8 expression is associated with a poorer prognosis of patients (Liss F et al. 2021). IRF8 regulates important signaling molecules such as the kinases SRC and FAK, the transcription factors RUNX1 and IRF5 as well as the cell cycle regulator cyclin D1.IRF8 could serve as a biomarker and potential molecular target in a subset of human AML in the future.

Immunodeficiency 32A (syn:IMD32A/ OMIM: 614893): autosomal dominant IRF8 deficiency causes an abnormal myeloid phenotype in peripheral blood with a marked loss of CD11C-positive dendritic cells. This dysfunction leads to a selective susceptibility to mycobacterial infections, an immune deficiency known as Mendelian susceptibility to mycobacterial disease (MSMD) (Hambleton et al. 2011). MSMD is a rare disorder characterized by a predisposition to disease caused by low virulent mycobacteria (e.g. BCG vaccines and environmental mycobacteria) in otherwise healthy individuals. MSMDs show no abnormalities in routine hematologic and immunologic tests. The term MSMD does not reflect all clinical features, as patients are also susceptible to salmonellosis, candidiasis and tuberculosis and, less frequently, infections with other intramacrophage bacteria, fungi or parasites and perhaps even some viruses.

Immunodeficiency 32B (syn:IMD32B/ OMIM: 226990): the autosomal recessive primary immunodeficiency characterized by recurrent infections resulting from variable defects in the development or function of immune cells, including monocytes, dendritic cells and natural killer (NK) cells. Patients are particularly susceptible to viral diseases (Mace et al. 2017).

1. Bustamante J et al. (2014) Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity. Semin Immunol 26:454-470.
2. DiNardo CD et al.(2016) Mutations in AML: prognostic and therapeutic implications. Hematol. Am Soc Hematol Educ Program 2016:348-355.
3. Hambleton S et al (2011) IRF8 mutations and human dendritic-cell immunodeficiency. New Eng. J Med 365: 127-138.
4. Liss F et al (2021) IRF8 Is an AML-Specific Susceptibility Factor That Regulates Signaling Pathways and Proliferation of AML Cells. Cancers (Basel) 13:764.
5. Mace EM et al (2017) Biallelic mutations in IRF8 impair human NK cell maturation and function. J Clin Invest 127: 306-320.