Expression of Interferon Regulatory Factor-4 (IRF4/MUM1) Is Associated with Inferior Overall Survival In Peripheral T-Cell Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 140-140
Author(s):  
Andrew L Feldman ◽  
Ahmet Dogan ◽  
Matthew J Maurer ◽  
Thomas M Habermann ◽  
Patrick B Johnston ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
T Cell ◽  
Prognostic Factor ◽  
Interferon Regulatory Factor ◽  
Minor Allele ◽  
Regulatory Factor ◽  
Poor Prognostic Factor ◽  
T Cell Lymphomas ◽  
Interferon Regulatory Factor 4

Abstract Abstract 140 Background: Peripheral T-cell lymphomas (PTCLs) have poor outcomes, and there is a lack of prognostic biomarkers and therapeutic targets to guide treatment. We recently proposed that the transcription factor, interferon regulatory factor-4 (IRF4, also called multiple myeloma oncogene-1 [MUM1]), might be oncogenic in PTCLs based on its expression in association with translocations between IRF4 and the T-cell receptor gene, TRA@. IRF4 is a therapeutic target in multiple myeloma, where high expression is a poor prognostic factor. In addition, at least two germline IRF4 single nucleotide polymorphisms (SNPs), rs12203592 and rs872071, are associated with IRF4 expression and disease risk and progression in various lymphoid neoplasms. However, the prognostic effects of IRF4/MUM1 expression and IRF4 SNPs in PTCLs are unknown. Methods: Forty seven newly diagnosed PTCL patients with available tissue were identified from the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource. There were 5 anaplastic large cell lymphomas, 14 cutaneous T-cell lymphomas (CTCLs), 6 cytotoxic T-cell lymphomas (cytTCLs: 4 extranodal NK/T-cell and 2 enteropathy type), and 22 PTCLs, not otherwise specified (NOS). Patients were diagnosed between September 2002 and February 2008 and systematically followed through March 2010 for overall survival (OS). Tumor cell IRF4/MUM1 expression was examined by immunohistochemistry on paraffin tissue sections (MUM1p clone; Dako). Positivity was defined as >30% of tumor cells with nuclear staining, as in previous studies. rs12203592 and rs872071 were genotyped in peripheral blood DNA. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for both IRF4/MUM1 expression and SNPs with OS. Chi-squared tests were used to assess the relationship between IRF4/MUM1 expression and IRF4 SNPs. Results: The median age at diagnosis was 60 years (range, 24–88). At a median follow-up of 62 months (range, 29–89), 22 (47%) of the patients had died. Fifteen (32%) of the 47 T-cell patients had IRF4/MUM1 positive tumors. IRF4/MUM1 positivity was associated with poorer overall survival (HR=4.3; 95% CI: 1.8–10.2; p=0.0008). This association was seen across PTCL subtypes, including PTCL, NOS (HR= 6.5; 95% CI: 1.5–27.7; p=0.01), CTCL (HR=13.4; 95% CI: 1.2–150.1; p=0.03), and cytTCL (HR=5.8; CI: 0.5–65.9; p=0.15). The minor allele (T) in SNP rs12203592 was positively associated with IRF4/MUM1 positivity in a dominant model, with IRF4/MUM1 expression in 60% of patients with CT or TT genotypes compared to 19% of patients with CC genotype (p=0.01). Patients with the CT/TT genotype at rs12203592 also had inferior overall survival (HR=3.7; 95% CI: 1.4–9.5; p=0.007). The rs872071 SNP showed no significant association with either IRF4/MUM1 expression (p=0.38) or overall survival (p=0.71). Conclusions: This study is the first to demonstrate that IRF4/MUM1 expression is poor prognostic factor in PTCLs. This association was observed across PTCL subtypes, including the most common subtype, PTCL, NOS. IRF4/MUM1 expression and poor survival in our patients also were associated with the minor allele (T) in the IRF4 SNP rs12203592; these findings are consistent with previous in vitro data showing the major allele (C) represses IRF4 promoter activity. Interestingly, rs872071 was not associated with IRF4/MUM1 expression or prognosis, similar to findings in multiple myeloma. In contrast, rs872071 is a risk and prognostic factor in chronic lymphocytic leukemia and classical Hodgkin lymphoma, diseases in which IRF4/MUM1 expression has been associated with favorable prognosis. IRF4/MUM1 expression is a poor prognostic factor in PTCLs. Disclosures: No relevant conflicts of interest to declare.

Copy Number Abnormalities Of The Interferon Regulatory Factor-4 (IRF4) Gene Are Associated With IRF4/MUM1 Expression In Peripheral T-Cell Lymphomas

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3016-3016
Author(s):  
Rebecca L Boddicker ◽  
Ryan A Knudson ◽  
Rhett P Ketterling ◽  
Law E Mark ◽  
Xiaoming Xing ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Sanger Sequencing ◽  
Cell Lymphoma ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
T Cell Lymphomas ◽  
Genetic Abnormalities ◽  
Interferon Regulatory Factor 4 ◽  
Peripheral T Cell Lymphomas

Abstract Background Peripheral T-cell lymphomas (PTCLs) are aggressive non-Hodgkin lymphomas with poor overall survival rates. The genetics of PTCLs are poorly understood. We have described t(6;14)(p25.3;q11.2) translocations in PTCLs involving the T-cell receptor-alpha (TRA@) and interferon regulatory factor-4 (IRF4) genes and overexpressing IRF4 protein (also called MUM1). IRF4/MUM1 is a lymphoid transcription factor involved in differentiation and growth, the expression of which is tightly regulated in normal T cells. However, nearly half of PTCLs constitutively express IRF4/MUM1 and this expression is associated with adverse overall survival in several PTCL subtypes. Because IRF4/TRA@ translocations are rare among PTCLs (<1%), we investigated the presence of other genetic abnormalities of IRF4 in PTCLs and examined their association with IRF4/MUM1 protein expression. Methods Studies were performed on paraffin tissue sections of PTCL specimens diagnosed by standard WHO criteria. IRF4/MUM1 immunohistochemical staining (IHC) was performed using the MUM1p antibody and considered positive if nuclear staining was present in >30% of tumor cell nuclei. Fluorescence in situ hybridization (FISH) was performed using breakapart probes constructed from bacterial artificial chromosome DNA that hybridized to loci flanking the IRF4 locus on 6p25.3. Cases with 3 or more fusion signals were considered to have extra copies of the IRF4 gene. In a subset of cases, PCR and Sanger sequencing was performed on DNA extracted from frozen PTCL tumor tissue with primer sets that amplified exons 1 to 10 of the IRF4 gene. Data were analyzed using the chi-square test or t test. Results PTCLs from 277 patients (175 M:102 F; median age, 61 y) were examined by both IHC and FISH. The subtype distribution was: PTCL, not otherwise specified (NOS), 93; anaplastic large cell lymphoma (ALCL), 89; angioimmunoblastic T-cell lymphoma (AITL), 27; cutaneous T-cell lymphoma (CTCL), 43; and cytotoxic PTCL, 25. IRF4/MUM1 was positive in 116 cases (42%). Extra copies of IRF4 were identified in 18 PTCLs (7%), 83% of which were IRF4/MUM1 protein-positive. In contrast, 39% of cases without extra copies of IRF4 were IRF4/MUM1 protein-positive (p=0.0002). The mean percentage of tumor cells with IRF4/MUM1 staining was 69% in cases with extra copies of IRF4, compared to 30% in cases without extra copies (p=0.0001). Extra copies of IRF4 were seen in 13% of ALCLs, 4% each of PTCLs, NOS and cytotoxic PTCLs, 2% of CTCLs, and 0% of AITLs (p=0.02). Two IRF4/MUM1-positive cases had an IRF4/TRA@ translocation (1%). We selected 30 IRF4/MUM1-positive PTCLs for Sanger sequencing. In this subset, we identified a previously undescribed non-synonymous variant in exon 5 (S309R) in 1 case (3%) without an extra copy of IRF4. Conclusions Extra copies of IRF4 are seen in ∼7% of PTCLs, are significantly associated with IRF4/MUM1 expression, and are preferentially observed in ALCLs. Both IRF4/TRA@ translocations and IRF4 mutations are rare in PTCLs. These data suggest that genetic abnormalities of the IRF4 gene – specifically extra copies of IRF4 – may contribute to IRF4/MUM1 expression in some PTCLs. Since IRF4/MUM1 expression is seen in ∼42% of PTCLs, these data also imply the existence of other regulatory mechanisms. Characterizing these mechanisms may be important clinically, since IRF4/MUM1 has been proposed as a therapeutic target in human cancers but drugs that directly inhibit its function are currently not available. Disclosures: No relevant conflicts of interest to declare.

Abstract 2323:Interferon regulatory factor-4is transcriptionally regulated by NF-κB in peripheral T-cell lymphomas

2014 ◽  
Author(s):  
Rebecca L. Boddicker ◽  
N. Sertac Kip ◽  
Luciana L. Almada ◽  
Julie C. Porcher ◽  
Deanna M. Grote ◽  
...  
Keyword(s):  
T Cell ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
T Cell Lymphomas ◽  
Peripheral T Cell Lymphomas

scholarly journals Interferon regulatory factor 4 as a therapeutic target in adult T-cell leukemia lymphoma

Retrovirology ◽  
2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Daniel A. Rauch ◽  
Sydney L. Olson ◽  
John C. Harding ◽  
Hemalatha Sundaramoorthi ◽  
Youngsoo Kim ◽  
...  
Keyword(s):  
T Cell ◽  
Therapeutic Target ◽  
Interferon Regulatory Factor ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Regulatory Factor ◽  
Adult T Cell Leukemia ◽  
Interferon Regulatory Factor 4

Multiple Myeloma Oncogene 1 (MUM1)/Interferon Regulatory Factor 4 (IRF4) Upregulates Monokine Induced by Interferon-gamma (MIG) Gene Expression in B-Cell Malignancy.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1111-1111
Author(s):  
Shinsuke Iida ◽  
Miyuki Uranishi ◽  
Takaomi Sanda ◽  
Takashi Ishida ◽  
Emi Tajima ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Cell Lines ◽  
Interferon Gamma ◽  
Zinc Finger Protein ◽  
B Cell Lymphoma ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
B Cell Lymphomas ◽  
Interferon Regulatory Factor 4

Abstract MUM1(multiple myeloma oncogene 1)/IRF4(interferon regulatory factor 4) is a transcription regulatory factor that is activated as a result of t(6;14)(p25;q32) in multiple myeloma. MUM1 expression is seen in various B-cell lymphomas/leukemias and has been reported to predict an unfavorable outcome in some lymphoma subtypes including diffuse large B-cell lymphoma (DLBCL) and B-cell chronic lymphocytic leukemia (B-CLL). To elucidate its role in B-cell malignancies, we prepared stably MUM1-expressing Ba/F3 cells, which proliferated at a higher rate than the parental cells, and performed cDNA microarray analysis to identify genes whose expression is regulated by MUM1. We found that the expression of four genes including FK506-binding protein 3 (FKBP3), the Monokine induced by interferon-gamma (MIG), Fas apoptotic inhibitory molecule (Faim) and Zinc finger protein 94 was altered in the MUM1-expressing cells. We then focused on MIG since its expression was immediately upregulated by MUM1 in inducible MUM1 expressing system. In reporter assays, MUM1 activated the MIG promoter in cooperation with PU.1, and the interaction between MUM1 and the MIG promoter sequence was confirmed in chromatin immunoprecipitation assay. The expression of MIG was correlated with that of MUM1 in B-CLL cell lines, and its receptor CXCR3 was also coexpressed in B-CLL cell lines that were positive for MUM1. Interestingly, treatment with neutralizing antibodies against MIG and its receptor, CXCR3, partially inhibited the proliferation of two MUM1-expressing B-CLL cell lines. These results suggest that MUM1 plays certain roles in the progression of B-cell lymphomas/leukemias by regulating the expression of various genes including MIG.

scholarly journals Modulation of T Cell Cytokine Production by Interferon Regulatory Factor-4

2002 ◽  
Vol 277 (51) ◽  
pp. 49238-49246 ◽  
Author(s):  
Chuan-Min Hu ◽  
So Young Jang ◽  
Jessica C. Fanzo ◽  
Alessandra B. Pernis
Keyword(s):  
T Cells ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Cytokine Production ◽  
Interferon Regulatory Factor ◽  
Luciferase Reporter ◽  
Regulatory Factor ◽  
A Site ◽  
Interferon Regulatory Factor 4 ◽  
Cell Cytokine Production

Production of cytokines is one of the major mechanisms employed by CD4+T cells to coordinate immune responses. Although the molecular mechanisms controlling T cell cytokine production have been extensively studied, the factors that endow T cells with their ability to produce unique sets of cytokines have not been fully characterized. Interferon regulatory factor (IRF)-4 is a lymphoid-restricted member of the interferon regulatory factor family of transcriptional regulators, whose deficiency leads to a profound impairment in the ability of mature CD4+T cells to produce cytokines. In these studies, we have investigated the mechanisms employed by IRF-4 to control cytokine synthesis. We demonstrate that stable expression of IRF-4 in Jurkat T cells not only leads to a strong enhancement in the synthesis of interleukin (IL)-2, but also enables these cells to start producing considerable amounts of IL-4, IL-10, and IL-13. Transient transfection assays indicate that IRF-4 can transactivate luciferase reporter constructs driven by either the human IL-2 or the human IL-4 promoter. A detailed analysis of the effects of IRF-4 on the IL-4 promoter reveals that IRF-4 binds to a site adjacent to a functionally important NFAT binding element and that IRF-4 cooperates with NFATc1. These studies thus support the notion that IRF-4 represents one of the lymphoid-specific components that control the ability of T lymphocytes to produce a distinctive array of cytokines.

Increased Cytotoxic T-Cell Infiltrates in the Bone Marrow Is an Independent Adverse Prognostic Factor in Patients with Newly Diagnosed Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1492-1492
Author(s):  
Grzegorz S. Nowakowski ◽  
Chin-Yang Li ◽  
David Dingli ◽  
Shaji Kumar ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Immune Response ◽  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
Prognostic Factor ◽  
Cytotoxic T Cells ◽  
Cytotoxic T Cell ◽  
Newly Diagnosed

Abstract Background: Cytotoxic T-cell infiltrates are a nearly universal finding in the bone marrow of patients with multiple myeloma. It has been postulated that presence of T-cells in the bone marrow of multiple myeloma (MM) patients represents an immune response against the tumor and therefore, might be associated with an improved prognosis. However, the impact of bone marrow T-cells on the prognosis of multiple myeloma patients has not been studied systematically. Methods: Bone marrow biopsies of patients with newly diagnosed multiple myeloma were stained by immnohistochemistry for the CD8 antigen and reviewed by a blinded hematopathologist. Three high power fields are reviewed for each biopsy and the total number of CD8 positive cells counted and reported. For patients with more than 300 cells per 3 fields, results were reported as &gt;300. The number of bone marrow CD8 positive cells was then correlated with patients’ clinical data, including other prognostic factors and overall survival. Results: Bone marrow biopsy specimens from 100 patients, performed within the week of a diagnosis of multiple myeloma and collected between May 1998 and January 2001 were evaluated. The median number of CD8 positive cells was 270 (33 – &gt;300). Patients’ characteristics are shown in Table 1. Median follow up was 30 months (0–80). The number of cytotoxic T-cells as a continuous variable was a risk factor for shortened overall survival, HR 1.86 (95% CI 1.11–3.35). Using minimal p value approach, the cutoff of 270 cells (the median) risk stratified patients into two groups: the median survival of patients with &gt; 270 CD8 positive cells was 16 months vs. 48 months in patients with ≤270 cells, p=0.005 (Figure). In multivariate analysis including age, B2M, albumin, CRP, bone marrow plasma cell percentage and plasma cell labeling index, the number of cytotoxic T-cells was an independent predictor of overall survival was HR 3.1, p=0.0017. Conclusion: We show that the number of cytotoxic T-cells in the bone marrow is a strong and independent prognostic factor in patients with newly diagnosed multiple myeloma. Our observation does not contradict the hypothesis that cytotoxic T-cells participate in an immune response against the tumor since our findings may represent a higher level of immune response associated with baseline aggressive disease biology. However, our study suggests for the first time that increased marrow cytotoxic T-cells have an adverse effect on outcome in myeloma, and suggest that these cells may have a direct facilitating effect on tumor growth and on the marrow microenvironment. Further studies of the biology of behind this observation are warranted. Characteristic N Median (range) Gender male 61 CRP 81 0.4mg/L (0.01–11.2) Albumin 99 3.6 g/dL (2.6–5.4) B2microglobulin 94 4.0 (0.9–28) μg/mL Marrow PC% 90 45% (11–99) PC labeling index 90 high (&gt;1%) 36 BM CD8 cells 100 270 (33 – &gt;300) ISS 94 1 19 2 41 3 34 Figure Figure

scholarly journals Interferon Regulatory Factor 4 Sustains CD8+ T Cell Expansion and Effector Differentiation

Immunity ◽  
2013 ◽  
Vol 39 (5) ◽  
pp. 833-845 ◽  
Author(s):  
Shuyu Yao ◽  
Bruno Fernando Buzo ◽  
Duy Pham ◽  
Li Jiang ◽  
Elizabeth J. Taparowsky ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Expansion ◽  
Cd8 T Cell ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
T Cell Expansion ◽  
Interferon Regulatory Factor 4

scholarly journals Th17 Cell-Mediated Colitis Is Positively Regulated by Interferon Regulatory Factor 4 in a T Cell-Extrinsic Manner

2021 ◽  
Vol 11 ◽  
Author(s):  
Vera Buchele ◽  
Patrick Konein ◽  
Tina Vogler ◽  
Timo Kunert ◽  
Karin Enderle ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Th17 Cell ◽  
Interferon Regulatory Factor ◽  
T Cell Subsets ◽  
Regulatory Factor ◽  
Th17 Response ◽  
Immune Mediated ◽  
Interferon Regulatory Factor 4

Inflammatory bowel diseases (IBDs) are characterized by chronic, inflammatory gastrointestinal lesions and often require life-long treatment with immunosuppressants and repetitive surgical interventions. Despite progress in respect to the characterization of molecular mechanisms e.g. exerted by TNF-alpha, currently clinically approved therapeutics fail to provide long-term disease control for most patients. The transcription factor interferon regulatory factor 4 (IRF4) has been shown to play important developmental as well as functional roles within multiple immune cells. In the context of colitis, a T cell-intrinsic role of IRF4 in driving immune-mediated gut pathology is established. Here, we conversely addressed the impact of IRF4 inactivation in non-T cells on T cell driven colitis in vivo. Employing the CD4+CD25− naïve T cell transfer model, we found that T cells fail to elicit colitis in IRF4-deficient compared to IRF4-proficient Rag1−/− mice. Reduced colitis activity in the absence of IRF4 was accompanied by hampered T cell expansion both within the mesenteric lymph node (MLN) and colonic lamina propria (cLP). Furthermore, the influx of various myeloids, presumably inflammation-promoting cells was abrogated overall leading to a less disrupted intestinal barrier. Mechanistically, gene profiling experiments revealed a Th17 response dominated molecular expression signature in colon tissues of IRF4-proficient, colitic Rag1−/− but not in colitis-protected Rag1−/−Irf4−/− mice. Colitis mitigation in Rag1−/−Irf4−/− T cell recipients resulted in reduced frequencies and absolute numbers of IL-17a-producing T cell subsets in MLN and cLP possibly due to a regulation of conventional dendritic cell subset 2 (cDC2) known to impact Th17 differentiation. Together, extending the T cell-intrinsic role for IRF4 in the context of Th17 cell driven colitis, the provided data demonstrate a Th17-inducing and thereby colitis-promoting role of IRF4 through a T cell-extrinsic mechanism highlighting IRF4 as a putative molecular master switch among transcriptional regulators driving immune-mediated intestinal inflammation through both T cell-intrinsic and T cell-extrinsic mechanisms. Future studies need to further dissect IRF4 controlled pathways within distinct IRF4-expressing myeloid cell types, especially cDC2s, to elucidate the precise mechanisms accounting for hampered Th17 formation and, according to our data, the predominant mechanism of colitis protection in Rag1−/−Irf4−/− T cell receiving mice.

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