The Role of IRF1 and IRF2 Transcription Factors in Leukaemogenesis

Abstract

Acute myeloid leukaemia (AML) is the most common form of leukaemia in adults. Although of the order of 75-85% of patients will achieve complete remission after induction chemotherapy, long-term survival is still relatively low. Despite the progress in the rational design of drugs in disorders such as chronic myeloid leukaemia, AML lacks a single specific pathogenomic event to act as a drug target. Interferon regulatory factor 1 (IRF1) is a member of a family of related proteins that act as transcriptional activators or repressors. IRF1 and its functional antagonist IRF2 originally discovered as transcription factors regulating the interferon-beta (IFN-beta) gene, are involved in the regulation of normal haematopoiesis and leukaemogenesis. IRF1 appears to act as a tumour suppressor gene and IRF2 as an oncogene. IRF1 acts to repress IRF2 function through the repression of cyclin-dependent kinase (CDK) inhibitor p21WAF1 critical for cell growth control. It appears that the tumour suppression function of IRF1 is abolished by IRF2. This review focuses on the interaction between IRF1 and IRF2 in myeloid development and leukaemogenesis, particularly in relation to the Ras signalling pathway. IRF2 may be a viable and specific therapeutic target in human leukaemia.

BAL1/ARTD9 represses the anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1-53 axes in diffuse large B-cell lymphoma

“…IRF1 mediates anti-proliferative and pro-apoptotic effects in cancer cells in a context-dependent and cell-type-specific manner (Choo et al, 2006). In the absence of antagonistic regulatory factors, increased expression and activation of IRF1 inhibits the expression of pro-survival members of the BCL2 family and simultaneously induces the expression and activation of proapoptotic and anti-proliferative gene products, including p53, p21 and CASP3 (Choo et al, 2006;Schwartz et al, 2011;Shi et al, 2011).…”

“…In the absence of antagonistic regulatory factors, increased expression and activation of IRF1 inhibits the expression of pro-survival members of the BCL2 family and simultaneously induces the expression and activation of proapoptotic and anti-proliferative gene products, including p53, p21 and CASP3 (Choo et al, 2006;Schwartz et al, 2011;Shi et al, 2011). IRF2, an antagonist of IRF1 is known to act as an oncogene product in various types of cancer and when overexpressed in cancer, IRF2 can abolish the tumor suppression function of IRF1 (Choo et al, 2006). Although loss of IRF1 alone is not associated with spontaneous tumor development in mice, it greatly increases tumor susceptibility in combination with loss of other tumor suppressor proteins such as p53 (Nozawa et al, 1999).…”

“…Recent studies demonstrated that IRF1 inhibits the expression of pro-survival members of the BCL2 family and induces the expression and activation of pro-apoptotic and antiproliferative gene products, including p53, p21 and CASP3 Tables S3, S4. (Choo et al, 2006;Schwartz et al, 2011;Shi et al, 2011). Conversely, it has been previously demonstrated that BCL6 can also suppress both the basal and the induced expression levels of tumor-suppressor genes PRDM1/BLIMP1 and p53, the cyclindependent kinase inhibitor gene p21 as well as the anti-apoptotic proto-oncogene BCL2 in DLBCL (Phan and Dalla-Favera, 2004;Saito et al, 2009).…”

Integrin-Mediated Actions of Thyroid Hormone Analogues on Tumor Cell Chemosensitivity, Integrin-Growth Factor Receptor Crosstalk and Inflammatory Gene Expression

“…The tetrac formulation reduced expression of several interferon response pathway genes, e.g., IRF5, but had only a minimally suppressive effect on IRF1. Interferon-regulatory factor 5 (IRF5) protein regulates macrophage contributions to inflammation and IRF1 functions as a tumor suppressor gene (Choo et al, 2006); thus, these tetrac actions have some coherence. Unmodified tetrac and nanotetrac both stimulated expression of SOCS4, the gene product of which is a suppressor of cytokine signaling.…”

Identification of biomarkers for ischemic cardiomyopathy based on microarray data analysis

“…diseases [40]. Recently, Chapin et al [41] indicated that the expression level of IRF1 was changed in the peripheral blood, which can be used as a marker to reflect the glucocorticoid response.…”