IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma

Ramos, Juan Carlos; Ruiz, Phillip; Ratner, Lee; Reis, Isildinha M.; Brites, Carlos; Pedroso, Célia; Byrne, Gerald E.; Toomey, Ngoc L.; Andela, Valentine B; Harhaj, Edward W.; Lossos, Izidore S.; Harrington, William J.

doi:10.1182/blood-2006-07-036368

Cited by 68 publications

(76 citation statements)

References 73 publications

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“…Among the mammalian IRFs, IRF4 is considered playing divers and important roles in the progress of lymphocyte development, via activating the lymphocyte differentiation related genes by individual or cooperation with other factors (Acquaviva et al, 2008; De Silva Eisenbeis et al, 1995;Huber and Lohoff, 2014;Ramos et al, 2007). Besides the transcription function, irf4 expression is also identified as a molecular checkpoint of B cell activation (Mittrucker et al, 1997;Yamagata et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Regulation pattern of fish irf4 (the gene encoding IFN regulatory factor 4) by STAT6, c-Rel and IRF4

Guo

et al. 2015

Developmental & Comparative Immunology

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Section: Discussionmentioning

confidence: 99%

Regulation pattern of fish irf4 (the gene encoding IFN regulatory factor 4) by STAT6, c-Rel and IRF4

Guo

et al. 2015

Developmental & Comparative Immunology

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“…The absence of a plateau phase in long-term PFS after CR with AZT-IFN confirms this therapy is suppressive, but not curative, which is evidenced by the persistence of minimal residual blood circulating malignant clones in serially analyzed long-term responders during progression-free periods. 18 Overall, these data support AZT-IFN as up-front therapy whenever feasible in patients with aggressive nonbulky nonlymphomatous ATLL; this approach would be particularly beneficial in patients who are not suitable for intensive chemotherapy or allo-HSCT.…”

Section: Org Frommentioning

confidence: 99%

“…As a local institutional practice, high-dose AZT (1.5 g or, more recently, 750 mg/m 2 , twice daily) and interferon-alfa-2b (IFN-a; 5-10 million units twice daily) were initiated and administered IV on an inpatient basis as previously reported. 18 In general, patients who responded continued to receive oral AZT 600 mg twice daily and subcutaneous IFN-a 5 million units once or twice daily as outpatients. For patients with prolonged clinical responses, these drugs were eventually tapered down to as low as AZT 300 mg twice daily and subcutaneous IFN-a 3 million units three times weekly as maintenance therapy.…”

Section: Treatment Regimensmentioning

confidence: 99%

Epidemiology, clinical features, and outcome of HTLV-1–related ATLL in an area of prevalence in the United States

Pimentel²,

et al. 2018

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“…[43][44][45] Among the NF-kB subunits, RelA (p65) has been implicated in DLBCL and multiple myeloma, 10,46,47 whereas c-Rel has been implicated as a driver of IRF4 in activated lymphocytes, in human T-lymphotropic virus-Itransformed cells, and in the human T-lymphotropic virus-I-associated neoplasm adult T-cell leukemia/lymphoma. [48][49][50] In PTCL, however, our data suggest that the alternative NF-kB pathway (p52 and RelB) [54][55][56] It would be of interest to examine retrospectively whether these responses were associated with IRF4 expression because biomarker-driven patient selection might increase response rates to NF-kB-targeted therapies. Nevertheless, our data should not be interpreted to suggest that the functional effects of NF-kB inhibition in PTCL cells are entirely IRF4 dependent, as the NF-kB complex is a master transcriptional regulator with a myriad of targets.…”

mentioning

confidence: 99%

The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma

Boddicker

Kip

Xing

et al. 2015

Blood

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• The NF-kB subunits p52 and RelB increase IRF4 promoter activity and expression in PTCL cells.• A positive feedback loop involving CD30, NF-kB, and IRF4 drives PTCL cell proliferation and can be blocked by NF-kB inhibitors.Peripheral T-cell lymphomas (PTCLs) are generally aggressive non-Hodgkin lymphomas with poor overall survival rates following standard therapy. One-third of PTCLs express interferon regulatory factor-4 (IRF4), a tightly regulated transcription factor involved in lymphocyte growth and differentiation. IRF4 drives tumor growth in several lymphoid malignancies and has been proposed as a candidate therapeutic target. Because direct IRF4 inhibitors are not clinically available, we sought to characterize the mechanism by which IRF4 expression is regulated in PTCLs. We demonstrated that IRF4 is constitutively expressed in PTCL cells and drives Myc expression and proliferation. Using an inhibitor screen, we identified nuclear factor kB (NF-kB) as a candidate regulator of IRF4 expression and cell proliferation. We then demonstrated that the NF-kB subunits p52 and RelB were transcriptional activators of IRF4. Further analysis showed that activation of CD30 promotes p52 and RelB activity and subsequent IRF4 expression. Finally, we showed that IRF4 transcriptionally regulates CD30 expression. Taken together, these data demonstrate a novel positive feedback loop involving CD30, NF-kB, and IRF4; further evidence for this mechanism was demonstrated in human PTCL tissue samples. Accordingly, NF-kB inhibitors may represent a clinical means to disrupt this feedback loop in IRF4-positive PTCLs. (Blood. 2015; 125(20):3118-3127) Introduction Peripheral T-cell lymphomas (PTCLs) are aggressive non-Hodgkin lymphomas (NHLs) characterized by poor overall survival rates. [1][2][3] Most patients are treated with anthracycline-based chemotherapy regimens originally designed for B-cell lymphomas. Five-year overall survival rates vary somewhat by subtype but average ;35%. The possibility of individualized targeted therapy holds promise, but advances have been hindered by the fact that few therapeutic targets have been identified and validated in PTCLs. Our group's approach to this challenge has been to characterize the genetics of PTCLs to identify novel biomarkers and therapeutic targets. We have focused particularly on chromosomal translocations, which have played a major role in identifying diagnostic, prognostic, and theranostic biomarkers in hematologic neoplasms in general (eg, BCR-ABL) and PTCLs specifically (ALK rearrangements). 4,5 We previously discovered a recurrent translocation in PTCL, t(6;14)(p25.3;q11.2), that juxtaposes the interferon regulatory factor-4 (IRF4) and T-cell receptor-a (TRA) genes and is associated with increased IRF4 expression. 6 Because TRA translocation partners typically function as oncogenes in T-cell malignancies, we postulated that IRF4 plays an oncogenic role in PTCLs.7 IRF4 is a tightly regulated transcription factor involved in growth and differentiation of normal T and B lymp...

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IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma

Cited by 68 publications

References 73 publications

Regulation pattern of fish irf4 (the gene encoding IFN regulatory factor 4) by STAT6, c-Rel and IRF4

Regulation pattern of fish irf4 (the gene encoding IFN regulatory factor 4) by STAT6, c-Rel and IRF4

Epidemiology, clinical features, and outcome of HTLV-1–related ATLL in an area of prevalence in the United States

The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma

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