IRF4

Gene Summary

Gene:IRF4; interferon regulatory factor 4
Aliases: MUM1, LSIRF, SHEP8, NF-EM5
Location:6p25.3
Summary:The protein encoded by this gene belongs to the IRF (interferon regulatory factor) family of transcription factors, characterized by an unique tryptophan pentad repeat DNA-binding domain. The IRFs are important in the regulation of interferons in response to infection by virus, and in the regulation of interferon-inducible genes. This family member is lymphocyte specific and negatively regulates Toll-like-receptor (TLR) signaling that is central to the activation of innate and adaptive immune systems. A chromosomal translocation involving this gene and the IgH locus, t(6;14)(p25;q32), may be a cause of multiple myeloma. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2010]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:interferon regulatory factor 4
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Lymphomat(6;14)(p25,q32) in Lymphomas
This translocation is seen in some B-cell non Hodgkin lymphomas, particular in diffuse large B-cell lymphoma.
View Publications43
-IRF4 and B-Cell Lymphoma View Publications41
Multiple Myelomat(6;14)(p25;q32) in Myeloma
This translocation juxtaposes the IgH locus to the IRF4 gene resulting in overexpressed of IRF4, which is thought to contribute to tumorigenesis in Myeloma.
View Publications12
Chronic Lymphocytic LeukemiaIRF4 and Chronic Lymphocytic Leukemia View Publications10
Hodgkin LymphomaIRF4 and Hodgkin Lymphoma View Publications10
MelanomaIRF4 and Melanoma View Publications9
Chronic Myelogenous LeukemiaIRF4 Expression in Chronic Myeloid Leukemia
Schmidt and colleagues (JCO, 2000) found that IRF4 was significantly downregulated in patients with CML compared to health subjects. Increasing IRF4 expression was associated with a favourable response to interferon Alfa therapy. This suggests that IRF4 expression may be a useful marker to monitor response to interferon Alfa in patients with CML.
View Publications4

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: IRF4 (cancer-related)

Oliveira CC, Maciel-Guerra H, Kucko L, et al.
Double-hit lymphomas: clinical, morphological, immunohistochemical and cytogenetic study in a series of Brazilian patients with high-grade non-Hodgkin lymphoma.
Diagn Pathol. 2017; 12(1):3 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Double-hit lymphomas (DHL) are rare high-grade neoplasms characterized by two translocations: one involving the gene MYC and another involving genes BCL2 or BCL6, whose diagnosis depends on cytogenetic examination. This research studied DHL and morphological and/or immunophenotypic factors associated with the detection of these translocations in a group of high-grade non-Hodgkin lymphoma cases.
METHOD: Clinical and morphological reviews of 120 cases diagnosed with diffuse large B-cell lymphoma and Burkitt lymphoma were conducted. Immunohistochemistry (CD20, CD79a, PAX5, CD10, Bcl6, Bcl2, MUM1, TDT and Myc) and fluorescence in situ hybridization for detection of MYC, BCL2 and BCL6 gene translocations were performed in a tissue microarray platform.
RESULTS: Three cases of DHL were detected: two with translocations of MYC and BCL2 and one with translocations of MYC and BCL6, all leading to death in less than six months. Among 90 cytogenetically evaluable biopsies, associations were determined between immunohistochemistry and fluorescence in situ hybridization for MYC (p = 0.036) and BCL2 (p = 0.001). However, these showed only regular agreement, indicated by Kappa values of 0.23 [0.0;0.49] and 0.35 [0.13;0.56], respectively. "Starry sky" morphology was strongly associated with MYC positivity (p = 0.01). The detection of three cases of DHL, all resulting in death, confirms the rarity and aggressiveness of this neoplasm.
CONCLUSIONS: The "starry sky" morphological pattern and immunohistochemical expression of Myc and Bcl2 represent possible selection factors for additional cytogenetic diagnostic testing.

Yang G, Deisch J, Tavares M, et al.
Primary B-cell lymphoma of the uterine cervix: Presentation in Pap-test slide and cervical biopsy.
Diagn Cytopathol. 2017; 45(3):235-238 [PubMed] Related Publications
This case involved a 69-year-old female who presented with irritative urinary voiding. Imaging studies showed an 18-cm uterine mass centering on the cervix and extending into the bladder. The Pap test slide demonstrated necrotic background and degenerative changes in single and grouped atypical "small round blue cells" with high nuclear/cytoplasm ratio, scant cytoplasm, and hyperchromatic focally cleaved nuclei with occasional nuclear membrane "snout projections." Cervical biopsies showed similar findings. The tumor cells were positive for CD45, CD20, and PAX-5, and negative with epithelial, neuroendocrine, and muscle markers. A Ki-67 immunostain showed a markedly elevated proliferative index and the MUM1 stain was diffusely positive. Molecular study identified clonal immunoglobulin heavy chain gene rearrangement. Owing to its rarity, cervical lymphoma may sometimes be confused with other types of malignant neoplasms or inflammatory processes. Therefore, it is important to recognize the cytological features of cervical lymphomas and be aware of the potential diagnostic pitfalls for timely diagnosis and therapy. Diagn. Cytopathol. 2017;45:235-238. © 2016 Wiley Periodicals, Inc.

Sakr H, Cruise M, Chahal P, et al.
Anaplastic lymphoma kinase positive large B-cell lymphoma: Literature review and report of an endoscopic fine needle aspiration case with tigroid backgrounds mimicking seminoma.
Diagn Cytopathol. 2017; 45(2):148-155 [PubMed] Related Publications
Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is a rare distinct type of non-Hodgkin's lymphoma that arises in association with alterations of the ALK gene. This distinct disease entity is typically associated with an aggressive clinical course and appears in light microscopic preparations as a monomorphic population of large, immunoblast-like cells. In this report, we describe a case of ALK+ LBCL diagnosed by transgastric endoscopic ultrasound-guided fine needle aspiration (EUS FNA) of splenic hilar lymph nodes. Modified Giemsa stained direct smears from the FNA sample demonstrated large lesional cells with foamy cytoplasm and macronucleoli admixed with small lymphocytes in tigroid backgrounds, mimicking the cytologic appearance of seminoma. Ancillary immunohistochemical studies subsequently confirmed the diagnosis of ALK+ LBCL with the lesional cells being immunoreactive for CD138, VS38c, MUM1, ALK1, and lambda light chain. The cohesiveness of the cells, the cellular morphology, and the tigroid backgrounds were all pitfalls for accurate diagnosis of this rare specific type of lymphoid malignancy by cytology. To our knowledge this is the first case report detailing the diagnosis of ALK+ LBCL by EUS FNA and the first report describing a glycogen-rich tigroid background in direct FNA smears. Establishing a refined diagnosis in cases of this rare form of LBCL is necessary, as therapies targeting ALK may be of value in clinical management. Diagn. Cytopathol. 2017;45:148-155. © 2016 Wiley Periodicals, Inc.

Wu M, Cao Y, Liu YL, et al.
Meta-analysis of the Correlation Between Interleukin-6 Promoter Polymorphism -174G/C and Interferon Regulatory Factor 4 rs12203592 Polymorphism With Skin Cancer Susceptibility.
Am J Ther. 2016 Nov/Dec; 23(6):e1758-e1767 [PubMed] Related Publications
Inflammation is a process whereby the immune system responds to a disease or injury. Chronic inflammation, however, has been linked to several types of cancers such as skin cancer. Molecular epidemiological studies were carried out in recent years evaluating interferon regulatory factor 4 (IRF4) rs12203592 and interleukin-6 (IL-6) gene -174G/C polymorphism associated with skin cancer risk for different groups of people. However, the results are still conflicting, not conclusive. We performed a meta-analysis to investigate the association between cancer susceptibility and IL-6 -174G/C (1130 cases and 1260 controls from 7 studies) and IRF4 rs12203592 polymorphisms (3879 cases and 6759 controls from 9 studies) in different inheritance models. We assess the strength of association of odds ratio (ORs), 95% confidence interval (CI). Overall, significantly elevated skin cancer risk was found when all studies were pooled into the meta-analysis of IL-6 -174G/C (For GC vs. GG: OR = 1.28, 95% CI, 1.06-1.54, I = 0, Pheterogeneity = 0.816; for CC/GC vs. GG: OR = 1.26, 95% CI, 1.05-1.50, I = 0, Pheterogeneity = 0.618). However, for IRF4 rs12203592 polymorphism, significantly increased risk of skin cancer was observed in TT versus CC (OR = 1.99, 95% CI, 1.30-3.07, I = 76.7%, Pheterogeneity < 0.001) and in recessive model (OR = 1.91, 95% CI, 1.31-2.77, I = 69.9%, Pheterogeneity < 0.001). This meta-analysis indicates that the IL-6 gene -174G/C and IRF4 rs12203592 polymorphisms may be associated with an increased skin cancer risk.

Batlle-López A, González de Villambrosía S, Francisco M, et al.
Stratifying diffuse large B-cell lymphoma patients treated with chemoimmunotherapy: GCB/non-GCB by immunohistochemistry is still a robust and feasible marker.
Oncotarget. 2016; 7(14):18036-49 [PubMed] Free Access to Full Article Related Publications
Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of aggressive lymphomas that can be classified into three molecular subtypes by gene expression profiling (GEP): GCB, ABC and unclassified. Immunohistochemistry-based cell of origin (COO) classification, as a surrogate for GEP, using three available immunohistochemical algorithms was evaluated in TMA-arranged tissue samples from 297 patients with de novo DLBCL treated by chemoimmunotherapy (R-CHOP and R-CHOP-like regimens). Additionally, the prognostic impacts of MYC, BCL2, IRF4 and BCL6 abnormalities detected by FISH, the relationship between the immunohistochemical COO classification and the immunohistochemical expression of MYC, BCL2 and pSTAT3 proteins and clinical data were evaluated. In our series, non-GCB DLBCL patients had significantly worse progression-free survival (PFS) and overall survival (OS), as calculated using the Choi, Visco-Young and Hans algorithms, indicating that any of these algorithms would be appropriate for identifying patients who require alternative therapies to R-CHOP. Whilst MYC abnormalities had no impact on clinical outcome in the non-GCB subtype, those patients with isolated MYC rearrangements and a GCB-DLBCL phenotype had worse PFS and therefore might benefit from novel treatment approaches.

Xu-Monette ZY, Zhang S, Li X, et al.
p63 expression confers significantly better survival outcomes in high-risk diffuse large B-cell lymphoma and demonstrates p53-like and p53-independent tumor suppressor function.
Aging (Albany NY). 2016; 8(2):345-65 [PubMed] Free Access to Full Article Related Publications
The role of p53 family member p63 in oncogenesis is the subject of controversy. Limited research has been done on the clinical implications of p63 expression in diffuse large B-cell lymphoma (DLBCL). In this study, we assessed p63 expression in de novo DLBCL samples (n=795) by immunohistochemistry with a pan-p63-monoclonal antibody and correlated it with other clinicopathologic factors and clinical outcomes. p63 expression was observed in 42.5% of DLBCL, did not correlate with p53 levels, but correlated with p21, MDM2, p16INK4A, Ki-67, Bcl-6, IRF4/MUM-1 and CD30 expression, REL gains, and BCL6 translocation. p63 was an independent favorable prognostic factor in DLBCL, which was most significant in patients with International Prognostic Index (IPI) >2, and in activated-B-cell-like DLBCL patients with wide- type TP53. The prognostic impact in germinal-center-B-cell-like DLBCL was not apparent, which was likely due to the association of p63 expression with high-risk IPI, and potential presence of ∆Np63 isoform in TP63 rearranged patients (a mere speculation). Gene expression profiling suggested that p63 has both overlapping and distinct functions compared with p53, and that p63 and mutated p53 antagonize each other. In summary, p63 has p53-like and p53-independent functions and favorable prognostic impact, however this protective effect can be abolished by TP53 mutations.

Zhao S, Dong X, Shen W, et al.
Machine learning-based classification of diffuse large B-cell lymphoma patients by eight gene expression profiles.
Cancer Med. 2016; 5(5):837-52 [PubMed] Free Access to Full Article Related Publications
Gene expression profiling (GEP) had divided the diffuse large B-cell lymphoma (DLBCL) into molecular subgroups: germinal center B-cell like (GCB), activated B-cell like (ABC), and unclassified (UC) subtype. However, this classification with prognostic significance was not applied into clinical practice since there were more than 1000 genes to detect and interpreting was difficult. To classify cancer samples validly, eight significant genes (MYBL1, LMO2, BCL6, MME, IRF4, NFKBIZ, PDE4B, and SLA) were selected in 414 patients treated with CHOP/R-CHOP chemotherapy from Gene Expression Omnibus (GEO) data sets. Cutoffs for each gene were obtained using receiver-operating characteristic curves (ROC) new model based on the support vector machine (SVM) estimated the probability of membership into one of two subgroups: GCB and Non-GCB (ABC and UC). Furtherly, multivariate analysis validated the model in another two cohorts including 855 cases in all. As a result, patients in the training and validated cohorts were stratified into two subgroups with 94.0%, 91.0%, and 94.4% concordance with GEP, respectively. Patients with Non-GCB subtype had significantly poorer outcomes than that with GCB subtype, which agreed with the prognostic power of GEP classification. Moreover, the similar prognosis received in the low (0-2) and high (3-5) IPI scores group demonstrated that the new model was independent of IPI as well as GEP method. In conclusion, our new model could stratify DLBCL patients with CHOP/R-CHOP regimen matching GEP subtypes effectively.

Gibbs DC, Orlow I, Bramson JI, et al.
Association of Interferon Regulatory Factor-4 Polymorphism rs12203592 With Divergent Melanoma Pathways.
J Natl Cancer Inst. 2016; 108(7) [PubMed] Article available free on PMC after 01/07/2017 Related Publications
BACKGROUND: Solar elastosis and neval remnants are histologic markers characteristic of divergent melanoma pathways linked to differences in age at onset, host phenotype, and sun exposure. However, the association between these pathway markers and newly identified low-penetrance melanoma susceptibility loci remains unknown.
METHODS: In the Genes, Environment and Melanoma (GEM) Study, 2103 Caucasian participants had first primary melanomas that underwent centralized pathology review. For 47 single-nucleotide polymorphisms (SNPs) previously identified as low-penetrant melanoma risk variants, we used multinomial logistic regression to compare melanoma with solar elastosis and melanoma with neval remnants simultaneously to melanoma with neither of these markers, excluding melanomas with both markers. All statistical tests were two-sided.
RESULTS: IRF4 rs12203592 was the only SNP to pass the false discovery threshold in baseline models adjusted for age, sex, and study center. rs12203592*T was associated positively with melanoma with solar elastosis (odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.18 to 1.82) and inversely with melanoma with neval remnants (OR = 0.65, 95% CI = 0.48 to 0.87) compared with melanoma with neither marker (P global = 3.78 x 10(-08)). Adjusting for phenotypic characteristics and total sun exposure hours did not materially affect rs12203592's associations. Distinct early- and late-onset age distributions were observed in patients with IRF4 rs12203592 [CC] and [TT] genotypes, respectively.
CONCLUSIONS: Our findings suggest a role of IRF4 rs12203592 in pathway-specific risk for melanoma development. We hypothesize that IRF4 rs12203592 could underlie in part the bimodal age distribution reported for melanoma and linked to the divergent pathways.

Peng Y, Zhao Q, Zhang H, et al.
TIPE2, a negative regulator of TLR signaling, regulates p27 through IRF4-induced signaling.
Oncol Rep. 2016; 35(4):2480-6 [PubMed] Related Publications
Targeted inhibition of specific toll-like receptor (TLR) pathways may provide an effective strategy to prevent the development of selected gastric malignancies. Tumor necrosis factor (TNF)-α-induced protein 8-like-2 (TIPE2) was identified as a novel negative regulator of TLR signaling. Our previous study identified TIPE2 as an inhibitor of gastric cancer cell growth; it promotes p27 expression, which leads to restored control of the cell cycle and cell division. However, the molecular mechanism by which TIPE2 regulates p27 remains unclear. In the present study, we examined the expression patterns of TIPE2 in serial clinical gastritis tissues as well as gastric cancer, and found a negative correlation between TIPE2 expression and progression of gastritis to gastric cancer. This negative correlation verified the role of TIPE2 in preventing the occurrence and development of gastric cancer, suggesting that TIPE2 may be a potential biomarker for gastric cancer progression. To determine the mechanism employed by TIPE2 in gastric cell carcinogenesis, a TIPE2-expressing plasmid was introduced into gastric cell lines, and microarray and western blot analysis revealed that TIPE2 selectively upregulates the expression of interferon regulatory factor 4 (IRF4). Variations in IRF4 expression were additionally verified in knockout mice. Next, the effect of IRF4 on p27 expression was tested by an IRF4 siRNA interference assay. Finally, we explored the signaling pathways used by TIPE2 to regulate IRF4. An experiment using pathway inhibitors and a nuclear factor κ-light-chain enhancer of activated B cells (NF-κB) luciferase reporter assay showed that NF-κB plays a crucial role in regulating IRF4 expression. Our data provide evidence that TIPE2, a potential biomarker for gastric cancer progression, stimulates an IRF4-associated signaling cascade that promotes p27 expression and controls cell growth. To the best of our knowledge, this is the first study to demonstrate that IRF4 acts as an inhibitor of epithelial cell proliferation and mediates the expression of TIPE2, a negative regulator of TLR signaling, to control cell growth.

Mehrian-Shai R, Yalon M, Moshe I, et al.
Identification of genomic aberrations in hemangioblastoma by droplet digital PCR and SNP microarray highlights novel candidate genes and pathways for pathogenesis.
BMC Genomics. 2016; 17:56 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
BACKGROUND: The genetic mechanisms underlying hemangioblastoma development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays and droplet digital PCR analysis to detect copy number variations (CNVs) in total of 45 hemangioblastoma tumors.
RESULTS: We identified 94 CNVs with a median of 18 CNVs per sample. The most frequently gained regions were on chromosomes 1 (p36.32) and 7 (p11.2). These regions contain the EGFR and PRDM16 genes. Recurrent losses were located at chromosome 12 (q24.13), which includes the gene PTPN11.
CONCLUSIONS: Our findings provide the first high-resolution genome-wide view of chromosomal changes in hemangioblastoma and identify 23 candidate genes: EGFR, PRDM16, PTPN11, HOXD11, HOXD13, FLT3, PTCH, FGFR1, FOXP1, GPC3, HOXC13, HOXC11, MKL1, CHEK2, IRF4, GPHN, IKZF1, RB1, HOXA9, and micro RNA, such as hsa-mir-196a-2 for hemangioblastoma pathogenesis. Furthermore, our data implicate that cell proliferation and angiogenesis promoting pathways may be involved in the molecular pathogenesis of hemangioblastoma.

Lorenzi L, Lonardi S, Essatari MH, et al.
Intrafollicular Epstein-Barr virus-positive large B cell lymphoma. A variant of "germinotropic" lymphoproliferative disorder.
Virchows Arch. 2016; 468(4):441-50 [PubMed] Related Publications
Germinotropic lymphoproliferative disorders were previously described as localized disorders associated with coinfection by human herpes virus 8 and Epstein-Barr virus and characterized by good clinical outcome. We report the clinical, morphological, phenotypical, and molecular features of three cases of a hitherto unreported variant of Epstein-Barr virus (EBV)-positive, human herpes virus 8 (HHV8)-negative large B cell lymphoma with exclusive intrafollicular localization. All cases occurred in elderly individuals (63, 77, and 65 years old; one male, two females) without obvious immunedeficiency, who presented with high stage disease. Lymph nodes showed an effaced nodular architecture with abnormal B follicles colonized by EBV+ large, pleomorphic atypical cells, including Reed-Sternberg-like cells, showing an activated B cell phenotype (CD10-FOXP1-Bcl6-IRF4+ or CD10-FOXP1+Bcl6+IRF4+) and intense expression of CD30. No monoclonal light-chain restriction was detected by immunohistochemistry or in situ hybridization, and IGH rearrangement was polyclonal; notably, EBV clonality was detectable in one case. Lymphoma cells in all cases showed diffuse expression of the c-Myc protein, while Bcl2 was dim or negative; moreover, the strong expression of phosphorylated-STAT3 in tumor cell nuclei suggested activation of the JAK-STAT pathway. FISH analysis was performed in two cases and showed no translocations of BCL2, BCL6, MYC, and PAX5 genes. Response to treatment was poor in 2/3 patients: one died after 18 months, one is alive with disease after 12 months. The intrafollicular EBV-positive large B cell lymphoma expands the spectrum of EBV-associated lymphoproliferative disorders in immunocompetent individuals.

Conery AR, Centore RC, Neiss A, et al.
Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma.
Elife. 2016; 5 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Selective targeting of multiple myeloma cell lines through CBP/EP300 bromodomain inhibition is the result of direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4, which is essential for the viability of myeloma cells, and the concomitant repression of the IRF4 target gene c-MYC. Ectopic expression of either IRF4 or MYC antagonizes the phenotypic and transcriptional effects of CBP/EP300 bromodomain inhibition, highlighting the IRF4/MYC axis as a key component of its mechanism of action. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network.

Ohguchi H, Hideshima T, Bhasin MK, et al.
The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival.
Nat Commun. 2016; 7:10258 [PubMed] Related Publications
KDM3A is implicated in tumorigenesis; however, its biological role in multiple myeloma (MM) has not been elucidated. Here we identify KDM3A-KLF2-IRF4 axis dependence in MM. Knockdown of KDM3A is toxic to MM cells in vitro and in vivo. KDM3A maintains expression of KLF2 and IRF4 through H3K9 demethylation, and knockdown of KLF2 triggers apoptosis. Moreover, KLF2 directly activates IRF4 and IRF4 reciprocally upregulates KLF2, forming a positive autoregulatory circuit. The interaction of MM cells with bone marrow milieu mediates survival of MM cells. Importantly, silencing of KDM3A, KLF2 or IRF4 both decreases MM cell adhesion to bone marrow stromal cells and reduces MM cell homing to the bone marrow, in association with decreased ITGB7 expression in MAF-translocated MM cell lines. Our results indicate that the KDM3A-KLF2-IRF4 pathway plays an essential role in MM cell survival and homing to the bone marrow, and therefore represents a therapeutic target.

Wang A, Welch R, Zhao B, et al.
Epstein-Barr Virus Nuclear Antigen 3 (EBNA3) Proteins Regulate EBNA2 Binding to Distinct RBPJ Genomic Sites.
J Virol. 2015; 90(6):2906-19 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
UNLABELLED: Latent infection of B lymphocytes by Epstein-Barr virus (EBV) in vitro results in their immortalization into lymphoblastoid cell lines (LCLs); this latency program is controlled by the EBNA2 viral transcriptional activator, which targets promoters via RBPJ, a DNA binding protein in the Notch signaling pathway. Three other EBNA3 proteins (EBNA3A, EBNA3B, and EBNA3C) interact with RBPJ to regulate cell gene expression. The mechanism by which EBNAs regulate different genes via RBPJ remains unclear. Our chromatin immunoprecipitation with deep sequencing (ChIP-seq) analysis of the EBNA3 proteins analyzed in concert with prior EBNA2 and RBPJ data demonstrated that EBNA3A, EBNA3B, and EBNA3C bind to distinct, partially overlapping genomic locations. Although RBPJ interaction is critical for EBNA3A and EBNA3C growth effects, only 30 to 40% of EBNA3-bound sites colocalize with RBPJ. Using LCLs conditional for EBNA3A or EBNA3C activity, we demonstrate that EBNA2 binding at sites near EBNA3A- or EBNA3C-regulated genes is specifically regulated by the respective EBNA3. To investigate EBNA3 binding specificity, we identified sequences and transcription factors enriched at EBNA3A-, EBNA3B-, and EBNA3C-bound sites. This confirmed the prior observation that IRF4 is enriched at EBNA3A- and EBNA3C-bound sites and revealed IRF4 enrichment at EBNA3B-bound sites. Using IRF4-negative BJAB cells, we demonstrate that IRF4 is essential for EBNA3C, but not EBNA3A or EBNA3B, binding to specific sites. These results support a model in which EBNA2 and EBNA3s compete for distinct subsets of RBPJ sites to regulate cell genes and where EBNA3 subset specificity is determined by interactions with other cell transcription factors.
IMPORTANCE: Epstein-Barr virus (EBV) latent gene products cause human cancers and transform B lymphocytes into immortalized lymphoblastoid cell lines in vitro. EBV nuclear antigens (EBNAs) and membrane proteins constitutively activate pathways important for lymphocyte growth and survival. An important unresolved question is how four different EBNAs (EBNA2, -3A, -3B, and -3C) exert unique effects via a single transcription factor, RBPJ. Here, we report that each EBNA binds to distinct but partially overlapping sets of genomic sites. EBNA3A and EBNA3C specifically regulate EBNA2's access to different RBPJ sites, providing a mechanism by which each EBNA can regulate distinct cell genes. We show that IRF4, an essential regulator of B cell differentiation, is critical for EBNA3C binding specificity; EBNA3A and EBNA3B specificities are likely due to interactions with other cell transcription factors. EBNA3 titration of EBNA2 transcriptional function at distinct sites likely limits cell defenses that would be triggered by unchecked EBNA2 prooncogenic activity.

Leich E, Hoster E, Wartenberg M, et al.
Similar clinical features in follicular lymphomas with and without breaks in the BCL2 locus.
Leukemia. 2016; 30(4):854-60 [PubMed] Related Publications
Approximately 15% of follicular lymphomas (FLs) lack breaks in the BCL2 locus. The aim of this study was to better define molecular and clinical features of BCL2-breakpoint/t(14;18)-negative FLs. We studied the presence of BCL2, BCL6 and MYC breaks by fluorescence in situ hybridization and the expression of BCL2, MUM1, CD10, P53 and Ki67 in large clinical trial cohorts of 540 advanced-stage FL cases and 116 early-stage disease FL patients treated with chemotherapy regimens and radiation, respectively. A total of 86% and 53% of advanced- and early-stage FLs were BCL2-breakpoint-positive, respectively. BCL2 was expressed in almost all FLs with BCL2 break and also in 86% and 69% of BCL2-breakpoint-negative advanced- and early-stage FLs, respectively. CD10 expression was significantly reduced in BCL2-breakpoint-negative FLs of all stages and MUM1 and Ki67 expression were significantly increased in BCL2-break-negative early-stage FLs. Patient characteristics did not differ between FLs with and without BCL2 breaks and neither did survival times in advanced-stage FLs. These results suggest that the molecular profile differs to some extent between FLs with and without BCL2 breaks and support the notion that FLs with and without BCL2 breaks belong to the same lymphoma entity.

Mareschal S, Dubois S, Viailly PJ, et al.
Whole exome sequencing of relapsed/refractory patients expands the repertoire of somatic mutations in diffuse large B-cell lymphoma.
Genes Chromosomes Cancer. 2016; 55(3):251-67 [PubMed] Related Publications
Despite the many efforts already spent to enumerate somatic mutations in diffuse large B-cell lymphoma (DLBCL), previous whole-genome and whole-exome studies conducted on patients of mixed outcomes failed at characterizing the 30% of patients who will relapse or resist current immunochemotherapies. To address this issue, we performed whole-exome sequencing of normal/tumoral DNA pairs in 14 relapsed/refractory (R/R) patients subclassified by full-transcriptome arrays (six activated B-cell like, three germinal center B-cell like, and five primary mediastinal B-cell lymphomas), from the LNH-03 LYSA clinical trial program. Aside from well-known DLBCL features, gene and pathway level recurrence analyses proposed several interesting leads including TBL1XR1 and activating mutations in IRF4 or in the insulin regulation pathway. Sequencing-based copy number analysis defined 23 short recurrently altered regions involving genes such as REL, CDKN2A, HYAL2, and TP53. Moreover, it highlighted mutations in genes such as GNA13, CARD11, MFHAS1, and PCLO as associated with secondary variant allele amplification events. The five primary mediastinal B-cell lymphomas (PMBL), while unexpected in a R/R cohort, showed a significantly higher mutation rate (P = 0.003) and provided many insights on this classical Hodgkin lymphoma related subtype. Novel genes such as XPO1, MFHAS1, and ITPKB were found particularly mutated, along with various cytokine-based signaling pathways. Among these analyses, somatic events in the NF-κB pathway were found preponderant in the three DLBCL subtypes, confirming its major implication in DLBCL aggressiveness and pinpointing several new candidate genes.

Dwivedi A, Mehta A, Solanki P
Evaluation of immunohistochemical subtypes in diffuse large B-cell lymphoma and its impact on survival.
Indian J Pathol Microbiol. 2015 Oct-Dec; 58(4):453-8 [PubMed] Related Publications
BACKGROUND AND AIM: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma in Indian population. The disease could be divided into the prognostically important subtypes, germinal center B-cell (GCB)-like and activated B-cell-like, using gene expression profiling (GEP). The molecular subtype as defined by GEP could also be predicted by using immunohistochemistry (IHC) based algorithms using three biomarkers CD10, BCL-6, and multiple myeloma oncogene-1 (MUM1). It has been confirmed that patients belonging to the GCB subtype have a better outcome and survival than those belonging to the second subtype. The present study was conducted to study the prevalence of these two subgroups and their correlation with survival of the patients.
MATERIALS AND METHODS: A total of 83 patients of DLBCL were included in the study. Hematoxylin- and eosin-stained sections were prepared from the paraffin-embedded tissue blocks. The staining for all the three antibodies was considered positive when more than 30% cells were stained with the respective antibody.
RESULTS: The results showed that 44 patients (53%) had GCB immunophenotype and 39 patients (47%) had non-GCB phenotype. However, no statistically significant difference in overall and disease-free survival was noted between the subgroups.
CONCLUSION: This study demonstrated that frequency of GCB subtype of DLBCL is significantly higher than the non-GCB subtype, and the non-GCB immunophenotype has better relapse-free survival 78% (standard error = 0.10) at the end of 3 years, while GCB has 56% (standard error = 0.23). Further studies should be performed with larger number of patients to show difference in clinical outcome between GCB and non-GCB subgroups.

Kuhlen M, Hönscheid A, Schemme J, et al.
Hodgkin lymphoma as a novel presentation of familial DICER1 syndrome.
Eur J Pediatr. 2016; 175(4):593-7 [PubMed] Related Publications
UNLABELLED: DICER1 germline mutations are associated with an inherited cancer syndrome, most commonly presenting with pleuropulmonary blastoma (PPB), ovarian sex cord tumors, thyroid cysts/goitre, and cystic nephroma. We describe the occurrence of a Hodgkin lymphoma (HL) of the T cell phenotype in a family with DICER1 syndrome. The patient presented with PPB Type I and HL. Immunohistochemical staining of the Hodgkin and Reed-Sternberg cells revealed CD30, TGP, CD2, CD3, CD15, and IRF4 positivity and weekly positivity of PAX5. T cell receptor repertoire analysis suggested HL of T cell origin, which is in contrast to common B cell-derived HL. The mother had been diagnosed with thyroid cysts, one sister had died from a primitive neuroectodermal tumor, and a brother had died from PPB Type III. Two mutational events were revealed in all affected family members; a single bp deletion, c.5299delC, leading to a frameshift and premature stop in exon 24 and a heterozygous variant (c.4616C>T; p.Thr1539Met) located in exon 23 of the DICER1 gene. This variant is predicted to be benign by in silico analysis.
CONCLUSION: Future studies looking for DICER1 mutations in HL cases of the T cell phenotype will be important to confirm its association with constitutional DICER1 syndrome.
WHAT IS KNOWN: • DICER1 germline mutations are associated with an inherited cancer syndrome, most commonly pleuropulmonary blastoma, ovarian sex cord tumors, thyroid cysts/goitre, and cystic nephroma. • Hodgkin lymphoma is one of the most frequent types of malignant lymphomas and typically arises sporadically. T cell-derived Hodgkin lymphomas are exceptionally rare. What is New: • DICER1 syndrome may have an even broader phenotypic spectrum and seems to be associated with rare forms of T cell Hodgkin lymphoma.

Kataoka K, Nagata Y, Kitanaka A, et al.
Integrated molecular analysis of adult T cell leukemia/lymphoma.
Nat Genet. 2015; 47(11):1304-15 [PubMed] Related Publications
Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-κB signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor.

Bjorklund CC, Lu L, Kang J, et al.
Rate of CRL4(CRBN) substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells by regulation of c-Myc and IRF4.
Blood Cancer J. 2015; 5:e354 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
Recent discoveries suggest that the critical events leading to the anti-proliferative activity of the IMiD immunomodulatory agents lenalidomide and pomalidomide in multiple myeloma (MM) cells are initiated by Cereblon-dependent ubiquitination and proteasomal degradation of substrate proteins Ikaros (IKZF1) and Aiolos (IKZF3). By performing kinetic analyses, we found that the downregulation or proteasomal degradation of Ikaros and Aiolos led to specific and sequential downregulation of c-Myc followed by IRF4 and subsequent growth inhibition and apoptosis. Notably, to ensure growth inhibition and cell death, sustained downregulation of Ikaros and Aiolos, c-Myc or IRF4 expression was required. In addition, we found that the half-maximal rate, rather than the final extent of Ikaros and Aiolos degradation, correlated to the relative efficacy of growth inhibition by lenalidomide or pomalidomide. Finally, we observed that all four transcription factors were elevated in primary MM samples compared with normal plasma cells. Taken together, our results suggest a functional link between Ikaros and Aiolos, and the pathological dysregulation of c-Myc and IRF4, and provide a new mechanistic understanding of the relative efficacy of lenalidomide and pomalidomide based on the kinetics of substrate degradation and downregulation of their downstream targets.

Choi YJ, Jung SH, Kim MS, et al.
Genomic landscape of endometrial stromal sarcoma of uterus.
Oncotarget. 2015; 6(32):33319-28 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
Although recurrent gene fusions such as JAZF1-JJAZ1 are considered driver events for endometrial stromal sarcoma (ESS) development, other genomic alterations remain largely unknown. In this study, we performed whole-exome sequencing, transcriptome sequencing and copy number profiling for five ESSs (three low-grade ESS (LG-ESS) and two undifferentiated uterine sarcomas (UUSs)). All three LG-ESSs exhibited either one of JAZF1-SUZ12, JAZF1-PHF1 and MEAF6-PHF1 fusions, whereas the two UUSs did not. All ESSs except one LG-ESS exhibited copy number alterations (CNAs), many of which encompassed cancer-related genes. In UUSs, five CNAs encompassing cancer-related genes (EZR, CDH1, RB1, TP53 and PRKAR1A) accompanied their expressional changes, suggesting that they might stimulate UUS development. We found 81 non-silent mutations (35 from LG-ESSs and 46 from UUSs) that included 15 putative cancer genes catalogued in cancer-related databases, including PPARG and IRF4 mutations. However, they were non-recurrent and did not include any well-known mutations, indicating that point mutations may not be a major driver for ESS development. Our data show that gene fusions and CNAs are the principal drivers for LG-ESS and USS, respectively, but both may require additional genomic alterations including point mutations. These differences may explain the different biologic behaviors between LG-ESS and UUS. Our findings suggest that ESS development requires point mutations and CNAs as well as the gene fusions.

Cozzolino I, Varone V, Picardi M, et al.
CD10, BCL6, and MUM1 expression in diffuse large B-cell lymphoma on FNA samples.
Cancer Cytopathol. 2016; 124(2):135-43 [PubMed] Related Publications
BACKGROUND: Gene expression profiling has divided diffuse large B-cell lymphoma (DLBCL) into 2 main subgroups: germinal center B (GCB) and non-GCB type. This classification is reproducible by immunohistochemistry using specific antibodies such as CD10, B-cell lymphoma 6 (BCL6), and multiple myeloma oncogene 1 (MUM1). Fine-needle aspiration (FNA) plays an important role in the diagnosis of non-Hodgkin lymphoma, and in some cases FNA may be the only available pathological specimen. The objectives of the current study were to evaluate CD10, BCL6, and MUM1 immunostaining on FNA samples by testing the CD10, BCL6, and MUM1 algorithm on both FNA cell blocks (CB) and conventional smears (CS), evaluating differences in CB and CS immunocytochemical (ICC) performance, and comparing results with histological data.
METHODS: Thirty-eight consecutive DLBCL cases diagnosed by FNA were studied. Additional passes were used to prepare CB in 22 cases and CS in 16 cases; the corresponding sections and smears were immunostained using CD10, BCL6, and MUM1 in all cases. The data obtained were compared with histological immunostaining in 24 cases.
RESULTS: ICC was successful in 33 cases (18 CB and 15 CS) and not evaluable in 5 cases (4 CB and 1 CS). The CD10-BCL6-MUM1 algorithm subclassified DLBCL as GCB (9 cases) and non-GCB (24 cases). ICC data were confirmed on histologic staining in 24 cases.
CONCLUSIONS: CD10, BCL6, and MUM1 ICC staining can be performed on FNA samples. The results herein prove it is reliable both on CB and CS, and is equally effective and comparable to immunohistochemistry data.

Kridel R, Mottok A, Farinha P, et al.
Cell of origin of transformed follicular lymphoma.
Blood. 2015; 126(18):2118-27 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
Follicular lymphoma (FL) is an indolent disease but transforms in 2% to 3% of patients per year into aggressive, large cell lymphoma, a critical event in the course of the disease associated with increased lymphoma-related mortality. Early transformation cannot be accurately predicted at the time of FL diagnosis and the biology of transformed FL (TFL) is poorly understood. Here, we assembled a cohort of 126 diagnostic FL specimens including 40 patients experiencing transformation (<5 years) and 86 patients not experiencing transformation for at least 5 years. In addition, we assembled an overlapping cohort of 155 TFL patients, including 114 cases for which paired samples were available, and assessed temporal changes of routinely available biomarkers, outcome after transformation, as well as molecular subtypes of TFL. We report that the expression of IRF4 is an independent predictor of early transformation (Hazard ratio, 13.3; P < .001). We also show that composite histology at the time of transformation predicts favorable prognosis. Moreover, applying the Lymph2Cx digital gene expression assay for diffuse large B-cell lymphoma (DLBCL) cell-of-origin determination to 110 patients with DLBCL-like TFL, we demonstrate that TFL is of the germinal-center B-cell-like subtype in the majority of cases (80%) but that a significant proportion of cases is of the activated B-cell-like (ABC) subtype (16%). These latter cases are commonly negative for BCL2 translocation and arise preferentially from BCL2 translocation-negative and/or IRF4-expressing FLs. Our study demonstrates the existence of molecular heterogeneity in TFL as well as its relationship to the antecedent FL.

Walker BA, Boyle EM, Wardell CP, et al.
Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma.
J Clin Oncol. 2015; 33(33):3911-20 [PubMed] Related Publications
PURPOSE: At the molecular level, myeloma is characterized by copy number abnormalities and recurrent translocations into the immunoglobulin heavy chain locus. Novel methods, such as massively parallel sequencing, have begun to describe the pattern of tumor-acquired mutations, but their clinical relevance has yet to be established.
METHODS: We performed whole-exome sequencing for 463 patients who presented with myeloma and were enrolled onto the National Cancer Research Institute Myeloma XI trial, for whom complete molecular cytogenetic and clinical outcome data were available.
RESULTS: We identified 15 significantly mutated genes: IRF4, KRAS, NRAS, MAX, HIST1H1E, RB1, EGR1, TP53, TRAF3, FAM46C, DIS3, BRAF, LTB, CYLD, and FGFR3. The mutational spectrum is dominated by mutations in the RAS (43%) and nuclear factor-κB (17%) pathways, but although they are prognostically neutral, they could be targeted therapeutically. Mutations in CCND1 and DNA repair pathway alterations (TP53, ATM, ATR, and ZNFHX4 mutations) are associated with a negative impact on survival. In contrast, those in IRF4 and EGR1 are associated with a favorable overall survival. We combined these novel mutation risk factors with the recurrent molecular adverse features and international staging system to generate an international staging system mutation score that can identify a high-risk population of patients who experience relapse and die prematurely.
CONCLUSION: We have refined our understanding of genetic events in myeloma and identified clinically relevant mutations that may be used to better stratify patients at presentation.

Fionda C, Abruzzese MP, Zingoni A, et al.
The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma.
Oncotarget. 2015; 6(27):23609-30 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
Immunomodulatory drugs (IMiDs) have potent anti-tumor activities in multiple myeloma (MM) and are able to enhance the cytotoxic function of natural killer (NK) cells, important effectors of the immune response against MM. Here, we show that these drugs can enhance the expression of the NKG2D and DNAM-1 activating receptor ligands MICA and PVR/CD155 in human MM cell lines and primary malignant plasma cells. Depletion of cereblon (CRBN) by shRNA interference strongly impaired upregulation of these ligands and, more interestingly, IMiDs/CRBN-mediated downregulation of the transcription factors Ikaros (IKZF1), Aiolos (IKZF3) and IRF4 was critical for these regulatory mechanisms. Indeed, shRNA knockdown of IKZF1 or IKZF3 expression was both necessary and sufficient for the upregulation of MICA and PVR/CD155 expression, suggesting that these transcription factors can repress these genes; accordingly, the direct interaction and the negative role of IKZF1 and IKZF3 proteins on MICA and PVR/CD155 promoters were demonstrated. Finally, MICA expression was enhanced in IRF4-silenced cells, indicating a specific suppressive role of this transcription factor on MICA gene expression in MM cells.Taken together, these findings describe novel molecular pathways involved in the regulation of MICA and PVR/CD155 gene expression and identify the transcription factors IKZF-1/IKZF-3 and IRF4 as repressors of these genes in MM cells.

Jovanovic MP, Mihaljevic B, Jakovic L, et al.
BCL2 positive and BCL6 negative diffuse large B cell lymphoma patients benefit from R-CHOP therapy irrespective of germinal and non germinal center B cell like subtypes.
J BUON. 2015 May-Jun; 20(3):820-8 [PubMed] Related Publications
PURPOSE: Despite major advances in the treatment of diffuse large B cell lymphoma (DLBCL), approximately one third of the patients progress or die, suggesting the existence of additional oncogenic events. The purpose of this study was to evaluate the prognostic value of the "Hans classifier", and BCL2 and MYC protein expression and gene alterations in DLBCL patients treated with CHOP or R-CHOP chemotherapy over a 5-year period. Furthermore, we tried to correlate these parameters with the International Prognostic Index (IPI).
METHODS: The immunohistochemical (IHC) expression of CD10, BCL6, MUM1 and BCL2 on paraffin-embedded formalin-fixed tumor samples from 103 centroblastic DLBCLs was analyzed. IHC expression of MYC and fluorescence in situ hybridization (FISH) for MYC and BCL2 gene alterations was performed on 67 samples using the tissue microarray (TMA) method.
RESULTS: The Hans algorithm was not predictive of survival in both therapy groups. No significant difference in BCL2 and MYC alterations or MYC protein expression in relation to complete response (CR), event-free survival (EFS) and overall survival (OS) was observed in our study. High IPI correlated significantly with poor outcome and it was identified as independent prognostic factor for OS and EFS (both p=0.000). The 5-year OS was 61% in the R-CHOP compared to 38% in the CHOP group (p=0.007). Rituximab significantly improved the OS in the BCL2 positive (60 vs 29%, p=0.008), and the BCL6 negative (73 vs 25%, p=0.001) cases.
CONCLUSION: IPI is an independent prognosticator for DL-BCL patients and the addition of rituximab significantly improved survival. Furthermore, patients with BCL2+ and BCL6-DLBCL benefited from R-CHOP.

Xie Z, Bi C, Chooi JY, et al.
MMSET regulates expression of IRF4 in t(4;14) myeloma and its silencing potentiates the effect of bortezomib.
Leukemia. 2015; 29(12):2347-54 [PubMed] Related Publications
Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. In t(4;14) MM, the MM SET domain (MMSET) protein is universally overexpressed and has been suggested to have an important tumorigenic role. However, the exact molecular targets underlying MMSET activity are not well understood. Here, we found in t(4;14) MM cells that MMSET knockdown decreases interferon regulatory factor 4 (IRF4) expression, and ectopic MMSET increases IRF4 expression, suggesting that MMSET is an upstream regulator of IRF4. Further analyses indicated an interaction between MMSET and nuclear factor-κB, which both bind to the IRF4 promoter region. A luciferase reporter assay showed that MMSET is an important functional element for the IRF4 promoter. MMSET knockdown induces apoptosis and potentiates the effects of bortezomib in vitro and in vivo. Importantly, we found that bortezomib could reduce expression of MMSET and IRF4. This might partly explain the additive effect of combining MMSET knockdown and bortezomib treatment. These results identify MMSET as a key regulator involved in the regulatory network of transcription factor IRF4, which is critical for MM cell survival, suggesting that the combination of MMSET inhibition and bortezomib is likely to improve patient outcome in MM.

Wagener R, Aukema SM, Schlesner M, et al.
The PCBP1 gene encoding poly(rC) binding protein I is recurrently mutated in Burkitt lymphoma.
Genes Chromosomes Cancer. 2015; 54(9):555-64 [PubMed] Related Publications
The genetic hallmark of Burkitt lymphoma is the translocation t(8;14)(q24;q32), or one of its light chain variants, resulting in IG-MYC juxtaposition. However, these translocations alone are insufficient to drive lymphomagenesis, which requires additional genetic changes for malignant transformation. Recent studies of Burkitt lymphoma using next generation sequencing approaches have identified various recurrently mutated genes including ID3, TCF3, CCND3, and TP53. Here, by using similar approaches, we show that PCBP1 is a recurrently mutated gene in Burkitt lymphoma. By whole-genome sequencing, we identified somatic mutations in PCBP1 in 3/17 (18%) Burkitt lymphomas. We confirmed the recurrence of PCBP1 mutations by Sanger sequencing in an independent validation cohort, finding mutations in 3/28 (11%) Burkitt lymphomas and in 6/16 (38%) Burkitt lymphoma cell lines. PCBP1 is an intron-less gene encoding the 356 amino acid poly(rC) binding protein 1, which contains three K-Homology (KH) domains and two nuclear localization signals. The mutations predominantly (10/12, 83%) affect the KH III domain, either by complete domain loss or amino acid changes. Thus, these changes are predicted to alter the various functions of PCBP1, including nuclear trafficking and pre-mRNA splicing. Remarkably, all six primary Burkitt lymphomas with a PCBP1 mutation expressed MUM1/IRF4, which is otherwise detected in around 20-40% of Burkitt lymphomas. We conclude that PCBP1 mutations are recurrent in Burkitt lymphomas and might contribute, in cooperation with other mutations, to its pathogenesis.

Gopalakrishnan R, Matta H, Tolani B, et al.
Immunomodulatory drugs target IKZF1-IRF4-MYC axis in primary effusion lymphoma in a cereblon-dependent manner and display synergistic cytotoxicity with BRD4 inhibitors.
Oncogene. 2016; 35(14):1797-810 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
Primary effusion lymphoma (PEL) is an aggressive type of non-Hodgkin lymphoma localized predominantly in body cavities. Kaposi's sarcoma-associated herpes virus (KSHV) is the causative agent of PEL. PEL is an incurable malignancy and has extremely poor prognosis when treated with conventional chemotherapy. Immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide are Food and Drug Administration-approved drugs for the treatment of various ailments. IMiDs display pronounced antiproliferative effect against majority of PEL cell lines within their clinically achievable concentrations, by arresting cells at G0/G1 phase of cell cycle and without any induction of KSHV lytic cycle reactivation. Although microarray examination of PEL cells treated with lenalidomide revealed activation of interferon (IFN) signaling, blocking the IFN pathway did not block the anti-PEL activity of IMiDs. The anti-PEL effects of IMiDs involved cereblon-dependent suppression of IRF4 and rapid degradation of IKZF1, but not IKZF3. Small hairpin RNA-mediated knockdown of MYC enhanced the cytotoxicity of IMiDs. Bromodomain (BRD) and extra-terminal domain (BET) proteins are epigenetic readers, which perform a vital role in chromatin remodeling and transcriptional regulation. BRD4, a widely expressed transcriptional coactivator, belongs to the BET family of proteins, which has been shown to co-occupy the super enhancers associated with MYC. Specific BRD4 inhibitors were developed, which suppress MYC transcriptionally. Lenalidomide displayed synergistic cytotoxicity with several structurally distinct BRD4 inhibitors (JQ-1, IBET151 and PFI-1). Furthermore, combined administration of lenalidomide and BRD4 inhibitor JQ-1 significantly increased the survival of PEL bearing NOD-SCID mice in an orthotopic xenograft model as compared with either agent alone. These results provide compelling evidence for clinical testing of IMiDs alone and in combination with BRD4 inhibitors for PEL.

Elyamany G, Alzahrani AM, Aljuboury M, et al.
Clinicopathologic features of plasmablastic lymphoma: Single-center series of 8 cases from Saudi Arabia.
Diagn Pathol. 2015; 10:78 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
BACKGROUND: Plasmablastic lymphoma (PBL) is a rare subtype of non-Hodgkin's lymphoma. Characterized by its aggressive nature and plasmacytic differentiation, PBL remains a therapeutic and diagnostic challenge; it generally has a poor prognosis with very few long-term survivors and most patients dying within 2 years from initial presentation. PBL has been reported in several other countries; however, there have been no reported cases from Saudi Arabia. Here, we report 8 cases of PBL depicting the clinical presentation, immunocompetency, immunphenotypic characterization, diagnostic challenges and treatment outcome.
METHODS: The medical records were reviewed for clinical presentation, staging, laboratory data, radiological studies, treatments, and outcomes. A broad immunohistochemical panel consisting of CD45, CD3, CD20, CD79a, Pax5, CD38, CD138, MUM1, EMA, Kappa, Lambda, CD 56, CD30, Bcl-2, Bcl-6, Alk-1, Ki-67, EBV-LMP-1, and HHV8 was performed.
RESULTS: The tumors predominantly exhibited immunoblastic/plasmablastic or plasmacytic morphologic features and had a plasma cell-like immunophenotype. All cases were immunoreactive for CD38, CD138 and MUM1 confirming plasma cell differentiation of the tumor cells. CD20 was negative for all cases; whereas CD79a and Pax5 were weakly positive in 2cases. All 8 cases were EBV-LMP-1/EBER-1 negative, and 1 case was HHV8 positive. Similar to previously published studies, PBL in Saudi Arabia is characterized by male predominance (6/8), median age 51.5 years (mean age 46 years), associated with early dissemination, poor response to therapy, and limited survival (average survival time, 6.4 months, median overall survival 5.5 months). However, it does have some unique features. It occurs more commonly in immunocompetent persons (6/8, 75%), is not associated with EBV infection (0/8), and nodal involvement (either primary or secondary) is common among patients (6/8). In addition, extra-oral sites are more common than oral/nasal cavities (7/8) and the c-myc gene is not common (1/8, 12.5%).
CONCLUSION: It appears that PBL is heterogeneous in terms of clinical presentation and morphology. PBL is a therapeutic challenge with a clinical course that is characterized by its high rate of relapse and death. To date, treatment responses are usually partial and temporary. Therapies that are more intensive than CHOP do not seem to prolong survival. Further research is needed to understand the biology and molecular pathogenesis of PBL in order to improve therapies.
VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1465801416161912.

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