Requirement for the Transcription Factor LSIRF/IRF4 for Mature B and T Lymphocyte Function

Mittrücker, Hans‐Willi; Matsuyama, Tomohiro; Grossman, Alex; Kündig, Thomas M.; Potter, Julia M.; Shahinian, Arda; Wakeham, Andrew; Patterson, Bruce; Ohashi, Pamela S.; Mak, Tak W.

doi:10.1126/science.275.5299.540

Cited by 541 publications

(513 citation statements)

References 20 publications

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“…In Table 2 the expression of investigated B-cell transcription factors in normal B-cell development is displayed. [12][13][14][15][16][17][18][19][20][21][22][23] Early B-Cell Transcription Factors: Pax-5 and PU.1 Expression…”

Section: Resultsmentioning

confidence: 99%

Expression of B-cell transcription factors in primary cutaneous B-cell lymphoma

et al. 2006

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Expression patterns of eight transcription factors involved in different stages of B-cell development were investigated in a large group of primary cutaneous B-cell lymphomas and compared with expression patterns during normal B-cell development. The following transcription factors were investigated: Pax-5, PU.1, Oct2, BOB.1, Bcl-6, Mum1/IRF4, Blimp-1 and FOXP1. Primary cutaneous large B-cell lymphomas, leg type showed aberrant coexpression of Bcl-6 and Mum1/IRF4 and in addition strong expression of FOXP1. Expression of FOXP1 and Mum1/IRF4 strongly suggests an activated B-cell type of origin. In contrast, primary cutaneous follicle center lymphomas showed expression of Bcl-6, Pax-5, PU.1, Oct2 and BOB.1, but not of Mum1/IRF4, Blimp-1 and FOXP1. Primary cutaneous marginal zone B-cell lymphoma showed expression of Pax-5, PU.1, Oct2 and BOB.1, but not Bcl-6 by the neoplastic B-cells, and Mum1/IRF4 and Blimp-1 by the neoplastic plasma cells. In conclusion, in primary cutaneous follicle center lymphoma and primary cutaneous marginal zone B-cell lymphoma expression patterns were observed similar to their supposed benign counterparts, germinal center B-cells and postgerminal center B-cells, respectively, which might reflect their indolent clinical behaviour and excellent prognosis. In contrast, the activated B-cell expression pattern in the group of primary cutaneous large B-cell lymphoma, leg type may contribute to its poor prognosis and Mum1/IRF4 and FOXP1 may serve as additional diagnostic markers for this type of primary cutaneous B-cell lymphoma.

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Section: Resultsmentioning

confidence: 99%

Expression of B-cell transcription factors in primary cutaneous B-cell lymphoma

et al. 2006

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“…Defects in IRF4/MUM1 expression result in defects in lymphocytes (T and B cell) and terminal differentiation of B cells toward plasma cells. 30 In addition, IRF4/MUM1 expression correlates with poor prognosis in various B-cell lymphoproliferative disorders. IRF4/MUM1 in cooperation with PU-1 enhances the transcription of the monokine induced by interferon-gamma (MIG) gene.…”

Section: Discussionmentioning

confidence: 99%

Higher response to lenalidomide in relapsed/refractory diffuse large B‐cell lymphoma in nongerminal center B‐cell–like than in germinal center B‐cell–like phenotype

Hernandez‐Ilizaliturri

Deeb

Zinzani

et al. 2011

Cancer

283

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BACKGROUND: There is a need to develop novel therapies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and to identify biomarkers predictive for therapeutic response. Lenalidomide was previously shown to induce an overall response rate (ORR) of 28% in patients with relapsed/refractory DLBCL. It is currently unknown if response rates differ between patients with different DLBCL subtypes. METHODS: The authors retrospectively evaluated clinical outcomes of patients with germinal center B-cell-like versus nongerminal center B-cell-like DLBCL treated with salvage lenalidomide at 4 academic institutions. RESULTS: Forty patients with relapsed/refractory DLBCL were included (24 men; 16 women; median age, 66 years; median of 4 prior treatments, including rituximab chemotherapy). Patients were classified as germinal center B-cell-like (n ¼ 23) or nongerminal center B-cell-like (n ¼ 17) DLBCL according to the Hans algorithm. The subgroups were similar in terms of stage, international prognostic index score, prior number of treatments, and rituximab resistance. A significant difference in clinical response to lenalidomide was observed in nongerminal center B-cell-like versus germinal center B-cell-like patients. ORR was 52.9% versus 8.7% (P ¼ .006); complete response rate was 23.5% versus 4.3%. Median progression-free survival was 6.2 versus 1.7 months (P ¼ .004), although no difference in OS was observed between nongerminal center B-cell-like and germinal center B-cell-like DLBCL patients. CONCLUSIONS: The data suggest that the 2 major subgroups of patients with DLBCL (germinal center B cell and nongerminal center B cell) have different antitumor responsiveness to lenalidomide in the relapsed/refractory setting. A large international trial (NCT01197560) has been opened to enrollment in an attempt to prospectively validate these retrospective observations. Cancer 2011;117:5058-

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“…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.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling in human gastric mucosa infected with Helicobacter pylori

et al. 2007

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Pathogenic mechanisms associated with Helicobacter pylori infection enhance susceptibility of the gastric epithelium to carcinogenic conversion. We have characterized the gene expression profiles of gastric biopsies from 69 French Caucasian patients, of which 43 (62%) were infected with H. pylori. The bacterium was detected in 27 of the 42 antral biopsies examined and in 16 of the 27 fundic biopsies. Infected biopsies were selected for the presence of chronic active gastritis, in absence of metaplasia and dysplasia of the gastric mucosa. Infected antral and fundic biopsies exhibited distinct transcriptional responses. Altered responses were linked with: (1) the extent of polymorphonuclear leukocyte infiltration, (2) bacterial density, and (3) the presence of the virulence factors vacA, babA2, and cagA. Robust modulation of transcripts associated with Toll-like receptors, signal transduction, the immune response, apoptosis, and the cell cycle was consistent with expected responses to Gram-negative bacterial infection. Altered expression of interferon-regulated genes (IFITM1, IRF4, STAT6), indicative of major histocompatibility complex (MHC) II-mediated and Th1-specific responses, as well as altered expression of GATA6, have previously been described in precancerous states. Upregulation of genes abundantly expressed in cancer tissues (UBD, CXCL13, LY96, MAPK8, MMP7, RANKL, CCL18) or in stem cells (IFITM1 and WFDC2) may reveal a molecular switch towards a premalignant state in infected tissues. Tissue microarray analysis of a large number of biopsies, which were either positive or negative for the cag-A virulence factor, when compared to each other and to noninfected controls, confirmed observed gene alterations at the protein level, for eight key transcripts. This study provides 'proof-of-principle' data for identifying molecular mechanisms driving H. pylori-associated carcinogenesis before morphological evidence of changes along the neoplastic progression pathway. Modern Pathology (2007) 20, 974-989;

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Requirement for the Transcription Factor LSIRF/IRF4 for Mature B and T Lymphocyte Function

Cited by 541 publications

References 20 publications

Expression of B-cell transcription factors in primary cutaneous B-cell lymphoma

Expression of B-cell transcription factors in primary cutaneous B-cell lymphoma

Higher response to lenalidomide in relapsed/refractory diffuse large B‐cell lymphoma in nongerminal center B‐cell–like than in germinal center B‐cell–like phenotype

Gene expression profiling in human gastric mucosa infected with Helicobacter pylori

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