Possible Involvement of Interferon Regulatory Factor 4 (IRF4) in a Clinical Subtype of Adult T‐Cell Leukemia

Abstract

Interferon regulatory factor (IRF) 4 is the lymphoid-specific transcription factor that is required for the proliferation of mitogen-activated T cells. IRF4 has been suggested to be involved in tumorigenesis because the overexpression of IRF4 caused the transformation of Rat-1 fibroblasts in vitro. Here, we show that IRF4 is constitutively expressed in adult T-cell leukemia (ATL)-derived cell lines, which were infected with human T-cell leukemia virus type-I, but hardly expressed the trans-activator protein, Tax. Similarly, constitutive expression of IRF4 was demonstrated in freshly isolated peripheral blood mononuclear cells (PBMC) from patients with either acute or chronic ATL. However, the high-level expression of IRF4 was specifically associated with acute ATL. With mitogen-activated PBMC from healthy donors, cell cycle analyses revealed that the induction of IRF4 occurred prior to cell cycle progression and the cells that had entered the cell cycle were predominantly IRF4-positive cells. In addition, ectopic expression of IRF4 in Rat-1 fibroblasts increased the S and G2/M phase population significantly. Taken together, our results indicate that IRF4 is involved in the pathogenesis of ATL through its positive effect on the cell cycle, and that IRF4 can be used as a molecular marker of clinical subtype in ATL.

Gene expression profiling in human gastric mucosa infected with Helicobacter pylori

“…Genetic studies have demonstrated that IRF-4 is a critical effector of mature lymphocyte function. 45 Imaizumi et al 46 have indicated that IRF-4 is involved in the pathogenesis of T-cell leukemia through its positive effect on the cell cycle, and that IRF-4 can be used as a molecular marker of clinical subtype in cell leukemia. An alternative explanation of altered expression of IFNg-regulated genes is provided by the fact that IFITM1 is notably associated with stem cells.…”

Repression of IRF-4 target genes in human T cell leukemia virus-1 infection

“…Thus the overall effect of IRF-4 in HTLV-1 infected cells is to contribute to the emergence of the transformed phenotype, increased survival and ATL cell metastasis (Figure 7). Recently, IRF-4 expression was also shown to increase during the clinical course of ATL, with expression levels elevated in patients with late stage, acute phase ATL (Imaizumi et al, 2001). IRF-4 may thus be a potential therapeutic target; ablation of IRF-4 levels may lead to a decrease in HTLV-1 T cell viability and prevent the onset of acute phase ATL.…”

“…IRF-4 was also shown to act synergistically with the v-Rel oncogene to transform fibroblasts (Hrdlickova et al, 2001). Interestingly, a recent report also suggests that IRF-4 expression increases during the development of ATL, with IRF-4 expression levels highest during the late and ultimately fatal, acute phase of ATL (Imaizumi et al, 2001).…”

“…Interestingly, one of the members of the interferon regulatory factor (IRF) family -IRF-4 -was shown to be highly expressed in cells derived from patients with ATL and in HTLV-1 infected cell lines (Imaizumi et al, 2001;Mamane et al, 1999Mamane et al, , 2000Mamane et al, , 2002Sharma et al, 2000Sharma et al, , 2002Yamagata et al, 1996). IRF-4 deficient mice develop severe phenotypes of immunodeficiencies (Mittrucker et al, 1997).…”

Multiple myeloma oncogene 1 (MUM1)/interferon regulatory factor 4 (IRF4) upregulates monokine induced by interferon-γ (MIG) gene expression in B-cell malignancy

“…Also, MUM1 is highly expressed in classical Hodgkin's lymphoma and in various types of T-cell lymphomas including adult T cell leukemia and anaplastic large-cell lymphoma. 12,13 Moreover, recently Genechip analysis demonstrated that MUM1 is preferentially clustered within the gene expression profile exhibited by activated B-cell(ABC)-like DLBCL, a subset of DLBCL associated with an unfavorable prognosis. 14 Other investigators have also found that MUM1 expression in DLBCL as detected by immunohistochemistry was associated with significantly worse survival.…”