IRF4: Immunity. Malignancy! Therapy?

Shaffer, Arthur L.; Emre, N. C. Tolga; Romesser, Paul B.; Staudt, Louis M.

doi:10.1158/1078-0432.ccr-08-1845

Cited by 169 publications

(156 citation statements)

References 89 publications

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“…The role of MUM-1 on MM pathogenesis is not clear because high expression of MUM-1 is also observed in normal plasma cells [23]. We found no influence of MUM-1 on OS in our series of patients.…”

contrasting

confidence: 60%

Increased expression of cyclin‐D1 on trephine bone marrow biopsies independently predicts for shorter overall survival in patients with multiple myeloma treated with novel agents

et al. 2012

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Multiple myeloma (MM) comprises 1% of all malignancies and 13% of hematological malignancies in the Caucasian population. Yearly incidence is 4/100,000 in the US and is higher in blacks and males [1]. The pathogenesis of the disease is relatively unknown; several chromosomal abnormalities have been related to the development of the disease, but none is characteristic of MM. Cyclin-D1 is a protein encoded by the CCND1 (bcl-1) gene on chromosome 11q13, and is an important regulator of G1 to S phase progression.Overexpression or overactivity of the CCND1 is common in malignancies including MM, mantle cell lymphoma, breast cancer, and hepatocellular cancer [2][3][4]. Previous studies have shown that CCND1 is expressed in 50% of patients with MM and that CCND1 overexpression represents an unfavorable prognostic factor in MM [5,6]. However, a recent study in a small number of patients showed that overexpressed CCND1 in MM is an independent prognostic marker associated with a more durable response to bortezomib. The aim of our study was to evaluate the impact of the immunohistochemical expression of cyclin-D1 in the plasma cells of trephine biopsies on survival of newly-diagnosed patients with MM who were treated with novel agents. One hundred and thirty consecutive patients with newly diagnosed MM were evaluated (66 males and 64 females). All patients were diagnosed, treated, and followed-up in a single center (Department of Clinical Therapeutics, University of Athens Medical School, Athens, Greece). Clinical characteristics of the patients are depicted in Table I. The median age of the patients was 68 years (range: 35-85 years). Forty-five patients (35%) had advanced disease at diagnosis (Stage 3 according to international staging system (ISS)). One hundred and fifteen patients (pts) had symptomatic disease that required therapy: 29 (25%) received bortezomib-based regimens (15 patients VTD (Bortezomib, Thalidomide and Dexamethasone), 5 patients VMP, and 5 patients PAD (Bortezomib, Doxorubicin and Dexamethasone)), 31 (26%) received thalidomide-based regimens (21 patients melphalan prednisone and thalidomide (MPT) and 10 patients thalidomide, vincristine, doxorubicin, dexamethasone (T-VAD)), and 55 received conventional treatment (20 patients VAD and 35 patients melphalan and prednisone) as first-line therapy, while all patients received regimens containing bortezomib or an immunomodulatory agents at some point during the course of their disease. Nineteen patients (16.5%) received high-dose melphalan plus autologous stem cell transplantation (ASCT). The median follow-up time for these patients was 22 months.Among patients with symptomatic myeloma (N 5 115), positive staining for cyclin-D1 (Fig. 1) was found in 35 (30%) patients, for CD56 in 45 (39%), for CD117 in 94 (81%), and for CD27 in 72 (62%) patients. In patients with asymptomatic/smoldering myeloma, positive staining for cyclin-D1 was found only in 1 (7%) patient, for CD56 in 9 (64%), and for CD117 in 6 (43%) (P < 0.01 for all comparisons compared to symptomatic...

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confidence: 60%

Increased expression of cyclin‐D1 on trephine bone marrow biopsies independently predicts for shorter overall survival in patients with multiple myeloma treated with novel agents

et al. 2012

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“…IRF-4 not only regulates genes that play crucial roles in normal hematopoetic cell development but is also involved with many genes regulating cell proliferation and survival in multiple myeloma (2). In particular, IRF-4 directly regulates the expression of MYC, which is essential for multiple myeloma cell survival (5).…”

Section: Discussionmentioning

confidence: 99%

“…2 plays a critical role in B, T, and dendritic cell development as well as in immune response regulation (1,2). IRF-4 was also originally identified as a proto-oncogene resulting from a t(6;14)(p25;q32) chromosomal translocation in multiple myeloma (3).…”

Section: Interferon Regulatory Factor 4 (Irf-4)mentioning

confidence: 99%

IRF-4 Suppresses BCR/ABL Transformation of Myeloid Cells in a DNA Binding-independent Manner

Ren

2012

Journal of Biological Chemistry

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Background: IRF-4 functions both as an oncoprotein and as a tumor suppressor in different cell context. Results: We found that IRF-4 inhibits BCR/ABL transformation of myeloid cells independent of its DNA binding and nuclear localization. Conclusion:The oncogenic and tumor suppressor functions of IRF-4 involve distinct pathways. Significance: The studies help to develop improved therapies for malignancies involving IRF-4.

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“…15,16 Mutations of TNFAIP3/A20 and CARD11 alterations also contribute to NF-kB pathway constitutive activation transactivating IRF4 in a positive feedback oncogenic loop. [17][18][19] Moreover, BLIMP1/PRDM1 inactivation by genetic loss or mutation was shown to disrupt post-germinal-center terminal B-cell differentiation. 20,21 We recently reported that primary cutaneous large B-cell lymphoma, leg type harbor at a striking elevated level (69%) a unique driver mutation (L265P) of MYD88 22 previously identified both at the genetic and functional level in 29% of activated B-cell-like nodal diffuse large B-cell lymphoma.…”

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confidence: 99%

Multiple genetic alterations in primary cutaneous large B-cell lymphoma, leg type support a common lymphomagenesis with activated B-cell-like diffuse large B-cell lymphoma

et al. 2014

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Primary cutaneous large B-cell lymphoma, leg type has been individualized from nodal diffuse large B-cell lymphoma. The objective of this study was to screen primary cutaneous large B-cell lymphoma, leg type for genetic alterations recently described in nodal diffuse large B-cell lymphoma. Skin biopsies from 23 patients were analyzed for IRF4, BCL2, BCL6, and MYC expression. FISH testing was performed for BCL2, BCL6, MYC with separation probes and for CDKN2A and PRDM1/BLIMP1 deletion. Multiple sequential FISH analyses with up to six probes were performed to define samples with multiple cytogenetic alterations. MYD88 mutations were studied by Sanger sequencing. All cases but one displayed at least one genetic alteration (96%). Nine patients exhibited a single genetic mutation and 12 combined several alterations (52%). We observed a split for BCL2, BCL6, or MYC in 1/23, 6/23, and 3/23 of cases, respectively. No double-hit lymphoma was observed. CDKN2A deletion was detected by FISH in only 5/23 cases. BLIMP1 and/or 6q deletion was observed at a higher rate in 10/20 of cases. No correlation between rearrangement and immunohistochemical expression was found for BCL2 or MYC. FISH tracking of sequential hybridizations showed that several alterations were carried by the same nuclei. The p.L265P MYD88 mutation was found in 11/18 (61%) of cases. Contrary to most cutaneous lymphomas that rarely harbor primary genetic alteration of their nodal histological equivalent, primary cutaneous large B-cell lymphoma, leg type seems to be a 'cutaneous counterpart' of activated B-cell-like diffuse large B-cell lymphoma with a similar cytogenetic profile and a high rate of MYD88 oncogenic L265P mutation. This also suggests a common lymphomagenesis with NF-jB activation, strong IRF4 expression and terminal B-cell differentiation blockage. Our data support the use of therapies targeting NF-jB, as most patients displayed disease progression and resistance to conventional therapies.

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IRF4: Immunity. Malignancy! Therapy?

Cited by 169 publications

References 89 publications

Increased expression of cyclin‐D1 on trephine bone marrow biopsies independently predicts for shorter overall survival in patients with multiple myeloma treated with novel agents

Increased expression of cyclin‐D1 on trephine bone marrow biopsies independently predicts for shorter overall survival in patients with multiple myeloma treated with novel agents

IRF-4 Suppresses BCR/ABL Transformation of Myeloid Cells in a DNA Binding-independent Manner

Multiple genetic alterations in primary cutaneous large B-cell lymphoma, leg type support a common lymphomagenesis with activated B-cell-like diffuse large B-cell lymphoma

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