NHL - Molecular Biology


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 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (36)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

TNFRSF8 1p36 CD30, Ki-1, D1S166E -TNFRSF8 and Non-Hodgkin Lymphoma
ALK 2p23 CD246, NBLST3 Translocation
-t(2;5)(p23;q35) NPM1-ALK translocation in Anaplastic large cell lymphoma
-ATIC-ALK Rearrangements in anaplastic large cell lymphoma
-ALK-CTCL Rearrangements in diffuse large B-cell lymphoma
NPM1 5q35.1 B23, NPM Translocation
-t(2;5)(p23;q35) NPM1-ALK translocation in Anaplastic large cell lymphoma
IGL 22q11.2 IGL@, IGLC6 -IGL and Non-Hodgkin Lymphoma
CCND3 6p21 -CCND3 and Non-Hodgkin Lymphoma
CCND2 12p13 MPPH3, KIAK0002 -CCND2 and Non-Hodgkin Lymphoma
FCGR3A 1q23 CD16, FCG3, CD16A, FCGR3, IGFR3, IMD20, FCR-10, FCRIII, FCGRIII, FCRIIIA -FCGR3A and Non-Hodgkin Lymphoma
RHOH 4p13 TTF, ARHH -RHOH and Non-Hodgkin Lymphoma
CXCR5 11q23.3 BLR1, CD185, MDR15 -CXCR5 and Non-Hodgkin Lymphoma
BRAF 7q34 NS7, BRAF1, RAFB1, B-RAF1 -BRAF and Non-Hodgkin's Lymphoma
ATIC 2q35 PURH, AICAR, AICARFT, IMPCHASE, HEL-S-70p -ATIC-ALK Rearrangements in anaplastic large cell lymphoma
-ATIC and Non-Hodgkin Lymphoma
LTA 6p21.3 LT, TNFB, TNFSF1 -LTA and Non-Hodgkin Lymphoma
IL4 5q31.1 BSF1, IL-4, BCGF1, BSF-1, BCGF-1 -IL4 and Non-Hodgkin Lymphoma
IGH 14q32.33 IGD1, IGH@, IGHJ, IGHV, IGHD@, IGHJ@, IGHV@, IGH.1@, IGHDY1 Translocation
-t(1;14)(q21;q32) BCL9/IGH
-t(1;14)(q21;q32) and MUC1 Overexpression in NHL
MUC1 1q21 EMA, MCD, PEM, PUM, KL-6, MAM6, MCKD, PEMT, CD227, H23AG, MCKD1, MUC-1, ADMCKD, ADMCKD1, CA 15-3, MUC-1/X, MUC1/ZD, MUC-1/SEC Translocation
-t(1;14)(q21;q32) and MUC1 Overexpression in NHL
SH2D1A Xq25 LYP, SAP, XLP, DSHP, EBVS, IMD5, XLPD, MTCP1, XLPD1, SAP/SH2D1A -SH2D1A and Non-Hodgkin Lymphoma
UCHL1 4p14 NDGOA, PARK5, PGP95, PGP9.5, Uch-L1, HEL-117, PGP 9.5 -UCHL1 and Non-Hodgkin Lymphoma
SHMT1 17p11.2 SHMT, CSHMT -SHMT1 and Non-Hodgkin Lymphoma
FCGR2A 1q23 CD32, FCG2, FcGR, CD32A, CDw32, FCGR2, IGFR2, FCGR2A1 -FCGR2A and Non-Hodgkin Lymphoma
LEPR 1p31 OBR, OB-R, CD295, LEP-R, LEPRD -LEPR and Non-Hodgkin Lymphoma
IL12A 3q25.33 P35, CLMF, NFSK, NKSF1, IL-12A -IL12A and Non-Hodgkin Lymphoma
CYBA 16q24 p22-PHOX -CYBA and Non-Hodgkin Lymphoma
PTPRJ 11p11.2 DEP1, SCC1, CD148, HPTPeta, R-PTP-ETA -PTPRJ and Non-Hodgkin Lymphoma
LTB 6p21.3 p33, TNFC, TNFSF3 -LTB and Non-Hodgkin Lymphoma
AKR1C1 10p15-p14 C9, DD1, DDH, DDH1, H-37, HBAB, MBAB, HAKRC, DD1/DD2, 2-ALPHA-HSD, 20-ALPHA-HSD -AKR1C1 and Non-Hodgkin Lymphoma
PTPRK 6q22.2-q22.3 R-PTP-kappa -PTPRK and Non-Hodgkin Lymphoma
PTPN1 20q13.1-q13.2 PTP1B -PTPN1 mutations in Hodgkin Lymphoma and PMBCL
BCL2L11 2q13 BAM, BIM, BOD -rs3789068 polymorphism BCL2L11 and increased risk of B-Cell NHL?
BCL6 3q27 BCL5, LAZ3, BCL6A, ZNF51, ZBTB27 Translocation
-t(3;14)(q27;q32) in B-cell non-Hodgkin's lymphoma
TSPYL2 Xp11.2 CDA1, CTCL, NP79, TSPX, CINAP, DENTT, SE204, HRIHFB2216 -ALK-CTCL Rearrangements in diffuse large B-cell lymphoma
RXRB 6p21.3 NR2B2, DAUDI6, RCoR-1, H-2RIIBP -RXRB and Non-Hodgkin Lymphoma
IDO1 8p12-p11 IDO, INDO, IDO-1 -IDO1 and Non-Hodgkin Lymphoma
PCSK7 11q23.3 LPC, PC7, PC8, SPC7 -PCSK7 and Non-Hodgkin Lymphoma
EIF4A2 3q28 DDX2B, EIF4A, EIF4F, BM-010, eIF4A-II, eIF-4A-II -EIF4A2 and Non-Hodgkin Lymphoma
BCL9 1q21 LGS Translocation
-t(1;14)(q21;q32) BCL9/IGH
BCL2 18q21.3 Bcl-2, PPP1R50 Translocation
-t(14;18)(q32;q21) in Non-Hodgkin's Lymphoma

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

Latest Publications

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.

Fernández C, Bellosillo B, Ferraro M, et al.
MicroRNAs 142-3p, miR-155 and miR-203 Are Deregulated in Gastric MALT Lymphomas Compared to Chronic Gastritis.
Cancer Genomics Proteomics. 2017; 14(1):75-82 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Over the last years, our knowledge on pathogenesis of gastric MALT lymphoma has greatly improved, but its morphological diagnosis is still hampered by overlapping histological features with advanced chronic gastritis. MicroRNAs are deregulated in lymphomas, but their role and usefulness in gastric MALT lymphoma has not been extensively investigated.
MATERIALS AND METHODS: We analyzed the expression of 384 miRNAs using TaqMan microRNA assay in a training series of 10 gastric MALT lymphomas, 3 chronic gastritis and 2 reactive lymph nodes. Then, significantly deregulated miRNAs were individually assessed by real-time PCR in a validation series of 16 gastric MALT lymphomas and 12 chronic gastritis.
RESULTS: Gastric MALT lymphoma is characterized by a specific miRNA expression profile. Among the differentially expressed miRNAs, a significant overexpression of miR-142-3p and miR-155 and down-regulation of miR-203 was observed in gastric MALT lymphoma when compared to chronic gastritis.
CONCLUSION: miR-142-3p, miR-155 and miR-203 expression levels might be helpful biomarkers for the differential diagnosis between gastric MALT lymphomas and chronic gastritis.

Miao Y, Lin P, Wang W, et al.
CCND1-IGH Fusion-Amplification and MYC Copy Number Gain in a Case of Pleomorphic Variant Mantle Cell Lymphoma.
Am J Clin Pathol. 2016; 146(6):747-752 [PubMed] Related Publications
OBJECTIVES: Mantle cell lymphoma (MCL) may present de novo or undergo progression to a clinically aggressive variant, known as a blastoid or pleomorphic variant. We report an unusual case of classic MCL in a 78-year-old man with a typical immunophenotype, including CD5 positivity, who subsequently relapsed with CD5-negative pleomorphic variant MCL.
METHODS: Biopsy specimens were evaluated using Wright-Giemsa-stained or H&E-stained sections, flow cytometry, immunohistochemistry, conventional cytogenetic, next-generation sequencing, and fluorescence in situ hybridization.
RESULTS: The patient continued to be refractory to intensive chemotherapy and radiation therapy. Initial conventional cytogenetic analysis showed a complex karyotype with amplification of the CCND1-IGH fusion gene on the der(14): 44, Y, t(X;2)(p22.3;q21), del(2)(p21), del(6)(p23), add(7)(p22),-9, del(9)(p22), add(11)(q13),-13, add(14)(p11.2), der(14)t(11;14)(q13;q32)hsr(14)(q32), add(18)(q23), add(21)(p11.1),-22,+mar[12]. A repeat biopsy revealed MCL, pleomorphic variant, with loss of CD5 expression and extra copies of the MYC CONCLUSIONS: CCND1-IGH fusion-amplification with MYC copy number gain is extremely rare and may play a role in disease progression in a subset of MCL cases.

Xu L, Zou XG, Wang X, et al.
Genetic characteristics of non-Hodgkin lymphoma in ethnic Uighur people, and their clinical significance.
Genet Mol Res. 2016; 15(4) [PubMed] Related Publications
The incidence of non-Hodgkin lymphoma (NHL) in China is increasing and is attracting attention as a topic of research. The percentage of NHL cases in ethnic Uighur people is also gradually increasing. We therefore recruited Uighur people with NHL to investigate the correlation between genetic alternations and clinical/pathological features in an attempt to determine their clinical significance. A total of 60 NHL patients were recruited from our hospital for a microscopic examination of their tumor cell morphology. Further analysis of chromosome karyotypes revealed the relationship between genetic alternations and clinical/pathological features. Microscopic examination revealed increased numbers of tumor cells with altered morphology. The recruited patients all exhibited abnormal karyotypes. Chromosomal breakages were detected at 14q32, 18q21, 6q21-25, +3, +, +18, and short tandem repeat 17 (str17) in 18.3, 25, 25, 18.3, 15, and 21.7% of patients, respectively. Karyotype change was not related to age, gender, performance status score, or pathological type (P > 0.05), but was correlated with clinical stage, average lactate dehydrogenase (LDH) level, extra-lymphatic metastasis, median survival time, and efficacy of radio- or chemotherapy (P < 0.05). Independent risk factors for genetic change in Uighur NHL patients included clinical stage, average LDH level, extra-lymphatic metastasis, median survival time, and efficacy of radio- or chemotherapy (P < 0.05). Uighur NHL patients exhibited genetic changes including t(14:18), 6q21-25, +3, +7, +18, and str17. Clinical stage, average LDH level, extra-lymphatic metastasis, median survival time, and efficacy of radio- or chemotherapy were all independent risk factors for NHL.

Liu D, Wang Y, Dong M, et al.
Polymorphisms in cytokine genes as prognostic markers in diffuse large B cell lymphoma patients treated with (R)-CHOP.
Ann Hematol. 2017; 96(2):227-235 [PubMed] Related Publications
To investigate whether cytokine genetic polymorphisms influence the outcome of diffuse large B cell lymphoma (DLBCL), we tested 337 consecutive DLBCL treated with CHOP or rituximab-CHOP (R-CHOP) from interleukin 10 (IL10), Bcl-2, and tumor necrosis factor (TNF)-α polymorphisms. Patients who carried the IL10 rs1800871 TT or rs1800872 AA genotype showed higher complete response (CR) and overall response rate (ORR) significantly. A longer progression-free survival (PFS) was observed in patients with IL10 rs1800871 TT (P = 0.017) or rs1800872 AA (P = 0.017) genotype after rituximab-based chemotherapy, and better PFS was also noted with Bcl-2 rs1801018 AA genotype in the CHOP group (P = 0.048). Furthermore, the R-CHOP group patients who carried the IL10 non-CCA haplotype had longer PFS (P = 0.030). Cox proportional hazards analyses demonstrated that the genotype TT of IL10 rs1800871 and AA plus AC of rs1800872 were predictive of longer PFS and event-free survival (EFS) in DLBCL patients treated with R-CHOP. And the Bcl-2 rs2279115 AA plus AC genotypes and rs1801018 GG genotype were risk factors for EFS in DLBCL patients treated with CHOP. In conclusion, the results reminded us those DLBCL patients with IL10 rs1800871 TT, rs1800872 AA, or IL10 non-CCA haplotype are likely to benefit from the therapy of rituximab-based chemotherapy.

Naeini YB, Wu A, O'Malley DP
Aggressive B-cell lymphomas: frequency, immunophenotype, and genetics in a reference laboratory population.
Ann Diagn Pathol. 2016; 25:7-14 [PubMed] Related Publications
Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma worldwide. The current World Health Organization classification includes several subtypes based on a combination of clinical, immunohistochemical, and genetic differences. Other aggressive variants of B-cell lymphomas, including Burkitt lymphoma and double-hit lymphomas are part of the differential diagnosis and often have overlapping features with DLBCL. In this study, we evaluated 760 of cases of DLBCL and other aggressive B-cell lymphomas using a relatively uniform immunohistochemical panel and genetic methods. We assessed the frequency of different subtypes and locations and documented distinctive immunophenotypic and genetic findings of these cases. Most cases in the study group were DLBCL (89%), including 38 CD5+ DLBCL, 28 T-cell/histiocyte-rich large B-cell lymphomas, and 33 Epstein-Barr virus-positive DLBCL (including 6 cases in elderly patients). The study also included 39 Burkitt lymphoma and 39 cases of double-hit lymphoma. In general, our results support the World Health Organization classification approach as well as other studies of DLBCL. In this study, we focus on specific issues of interest including cell-of-origin classification testing, comparing the Hans classifier with the tally classifier, correlation of MYC immunohistochemistry with MYC fluorescence in situ hybridization, and Epstein-Barr virus positivity in aggressive B-cell lymphomas.

Zheng Z, Li X, Zhu Y, et al.
Prognostic Significance of MiRNA in Patients with Diffuse Large B-Cell Lymphoma: a Meta-Analysis.
Cell Physiol Biochem. 2016; 39(5):1891-1904 [PubMed] Related Publications
INTRODUCTION: This pooled analysis study aimed to reveal the prognostic relevance of microRNAs (miRNAs) in patients with diffuse large B-cell lymphoma (DLBCL).
MATERIALS AND METHODS: We examined the impact of miRNAs on clinical outcome. Eligible studies were identified and quality assessed using multiple search strategies. Data were extracted from included studies which correlated survival with expression of miRNAs (serum or tissue).
RESULTS: We pooled proper studies, and combined the hazard ratios with 95% confidence intervals to estimate strength of the correlations. There were 18 studies including 1950 patients with DLBCL eligible for pooled analysis. We found significant combined HRs for poor overall survival for high expression of miR-21 and low expression of miR-224 in tumor tissue, but for favorable relapse free survival for high expression of miR-21 in serum. Progression free survival was shortened in patients with low expression of miR-199a/b, miR-146b-5p, miR-224 and high expression of miR-222.
CONCLUSION: MiRNAs may act as independent prognostic factors in patients with DLBCL, and useful in risk stratification.

Benoit BM, Jariwala N, O'Connor G, et al.
CD164 identifies CD4(+) T cells highly expressing genes associated with malignancy in Sézary syndrome: the Sézary signature genes, FCRL3, Tox, and miR-214.
Arch Dermatol Res. 2017; 309(1):11-19 [PubMed] Related Publications
Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), is associated with a significantly shorter life expectancy compared to skin-restricted mycosis fungoides. Early diagnosis of SS is, therefore, key to achieving enhanced therapeutic responses. However, the lack of a biomarker(s) highly specific for malignant CD4(+) T cells in SS patients has been a serious obstacle in making an early diagnosis. We recently demonstrated the high expression of CD164 on CD4(+) T cells from Sézary syndrome patients with a wide range of circulating tumor burdens. To further characterize CD164 as a potential biomarker for malignant CD4(+) T cells, CD164(+) and CD164(-)CD4(+) T cells isolated from patients with high-circulating tumor burden, B2 stage, and medium/low tumor burden, B1-B0 stage, were assessed for the expression of genes reported to differentiate SS from normal controls, and associated with malignancy and poor prognosis. The expression of Sézary signature genes: T plastin, GATA-3, along with FCRL3, Tox, and miR-214, was significantly higher, whereas STAT-4 was lower, in CD164(+) compared with CD164(-)CD4(+) T cells. While Tox was highly expressed in both B2 and B1-B0 patients, the expression of Sézary signature genes, FCRL3, and miR-214 was associated predominantly with advanced B2 disease. High expression of CD164 mRNA and protein was also detected in skin from CTCL patients. CD164 was co-expressed with KIR3DL2 on circulating CD4(+) T cells from high tumor burden SS patients, further providing strong support for CD164 as a disease relevant surface biomarker.

Soon G, Ow GW, Chan HL, et al.
Primary cardiac diffuse large B-cell lymphoma in immunocompetent patients: clinical, histologic, immunophenotypic, and genotypic features of 3 cases.
Ann Diagn Pathol. 2016; 24:40-6 [PubMed] Related Publications
Primary cardiac lymphoma (PCL) is a rare extranodal lymphoma that involves only the heart and/or pericardium. Primary cardiac lymphoma is much less common in immunocompetent patients compared with those who are immunosuppressed. Patients with PCL have variable clinical manifestations that may lead to misdiagnosis and delay in treatment. Modern radiologic imaging now allows for earlier detection of these tumors. This study describes the clinical, histologic/cytologic, immunophenotypic, and molecular genetic findings for 3 immunocompetent patients with primary cardiac diffuse large B-cell lymphoma. All 3 patients had different initial clinical presentations. The neoplastic cells in all 3 cases were large in size, morphologically resembling diffuse large B-cell lymphoma. Neoplastic cells in 2 cases had non-germinal center (GC)-like (non-GC-like) and 1 case had GC-like immunophenotype. Neoplastic cells in all 3 cases showed C-MYC and BCL2 immunohistochemical protein coexpression. Neoplastic cells in 1 case showed double-hit MYC and BCL2 gene rearrangements, whereas another 1 case showed MYC gene rearrangement without BCL2 gene rearrangement. Epstein-Barr virus-encoded RNA was negative in the neoplastic cells in all 3 cases. All 3 patients received rituximab-based chemotherapy. Two patients subsequently had disease relapse at other extranodal sites at 10 and 24 months, respectively, whereas 1 patient was alive without disease at 9 months after diagnosis. If there is sufficient diagnostic tissue in these rare tumors, molecular studies should ideally be performed for prognostication and further patient management.

Papadavid E, Braoudaki M, Bourdakou M, et al.
Aberrant microRNA expression in tumor mycosis fungoides.
Tumour Biol. 2016; 37(11):14667-14675 [PubMed] Related Publications
Herein, miRNA candidates relevant to mycosis fungoides were investigated to provide data on the molecular mechanisms underlying the pathogenesis of the disease. The miRNA expression profile of skin biopsies from patients with tumor stage MF (tMF) and normal donors was compared using miRNA microarrays. Overall, 154 miRNAs were found differentially expressed between tMF and the control cohort with the majority of them being up-regulated (57 %). Among the upregulated miRNAs, miR-3177, miR-514b-3p, miR-1267, and miR-1282 were exclusively detected in 70 % of tMF. Additional upregulated miRNAs included miR-34a, miR-29a, let-7a*, and miR-210, while miR-200c* was identified among the downregulated ones. Quantitative real-time polymerase chain reaction was used to further investigate the expression profiles of miR-34a and miR-29a and validated the overexpression of miR-34a. Enrichment studies revealed that the target genes of the differentially expressed miRNAs were important in several cancer-related signaling pathways. The overlapping relationship of the target genes among tMF, Sezary syndrome, and atopic dermatitis revealed several common and disease-specific genes. Collectively, our study modulated miR-34a as a candidate oncogenic molecule and miR-29a as a putative tumor suppressor highlighting their promising potential in the molecular pathogenesis of tMF.

Gallo M, Cacheux V, Vincent L, et al.
Leukemic non-nodal mantle cell lymphomas have a distinct phenotype and are associated with deletion of PARP1 and 13q14.
Virchows Arch. 2016; 469(6):697-706 [PubMed] Related Publications
Leukemic non-nodal mantle cell lymphoma (lMCL) is a particular subtype of mantle cell lymphoma (MCL), characterized by leukemic non-nodal disease and slow progression. Recognition of this entity is relevant to avoid overtreatment. Despite indolent clinical behaviour, lMCL might transform to a more aggressive disease. The purpose of this study was to compare lMCL with classical MCL (cMCL) and aggressive MCL (aMCL) using immunohistochemistry, interphase fluorescence in situ hybridization (FISH), and array-based comparative genomic hybridization, in order to identify biomarkers for lMCL diagnosis and prognosis. Seven lMCL patients were included. All had bone marrow involvement without lymphadenopathy. An lMCL phenotype was distinct from that of cMCL and aMCL: SOX11-, ATM+, PARP1+/-, and low KI67 (average 2 %). Beyond the t(11;14) translocation, fewer secondary cytogenetic alterations were found in lMCL compared to cMCL and aMCL, including deletion of PARP1 and 13q14. At last follow-up, one patient with lMCL had died of disease and another had progressive disease. These patients were respectively 13q14 deletion- and PARP1-positive. One other case of lMCL harbored a 13q14 deletion associated with PARP1 deletion. This patient had indolent disease. lMCL has a particular phenotype and fewer secondary cytogenetic alterations than cMCL and aMCL. PARP1 protein expression and 13q14 deletion are associated with a progressive clinical course of lMCL and should be included in initial diagnostic studies as predictors of unfavorable outcome. PARP1 deletion is involved in lMCL pathogenesis and might confer advantage.

Takahara T, Matsuo K, Seto M, et al.
Synergistic activity of Card11 mutant and Bcl6 in the development of diffuse large B-cell lymphoma in a mouse model.
Cancer Sci. 2016; 107(11):1572-1580 [PubMed] Free Access to Full Article Related Publications
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma; it derives from germinal center B cells. Although DLBCL harbors many genetic alterations, synergistic roles between such alterations in the development of lymphoma are largely undefined. We previously established a mouse model of lymphoma by transplanting gene-transduced germinal center B cells into mice. Here, we chose one of the frequently mutated genes in DLBCL, Card11 mutant, to explore its possible synergy with other genes, using our lymphoma model. Given that BCL6 and BCL2 expression and/or function are often deregulated in human lymphoma, we examined the possible synergy between Card11, Bcl6, and Bcl2. Germinal center B cells were induced in vitro, transduced with Card11 mutant, Bcl6, and Bcl2, and transplanted. Mice rapidly developed lymphomas, with exogenously transduced Bcl2 being dispensable. Although some mice developed lymphoma in the absence of transduced Bcl6, the absence was compensated by elevated expression of endogenous Bcl6. Additionally, the synergy between Card11 mutant and Bcl6 in the development of lymphoma was confirmed by the fact that the combination of Card11 mutant and Bcl6 caused lymphoma or death significantly earlier and with higher penetrance than Card11 mutant or Bcl6 alone. Lymphoma cells expressed interferon regulatory factor 4 and PR domain 1, indicating their differentiation toward plasmablasts, which characterize activated B cell-like DLBCL that represents a clinically aggressive subtype in humans. Thus, our mouse model provides a versatile tool for studying the synergistic roles of altered genes underlying lymphoma development.

Garaicoa FH, Roisman A, Arias M, et al.
Genomic imbalances and microRNA transcriptional profiles in patients with mycosis fungoides.
Tumour Biol. 2016; 37(10):13637-13647 [PubMed] Related Publications
Mycosis fungoides is the most common type of primary cutaneous T cell lymphoma. We have evaluated CDKN2A losses and MYC gains/amplifications by FISH analysis, as well as expression of miR-155 and members of the oncogenic cluster miR-17-92 (miR17, miR18a, miR19b, and miR92a) in MF patients with advanced disease. Formalin-fixed paraffin-embedded skin biopsies from 36 patients at diagnosis, 16 with tumoral MF (T-MF), 13 in histological transformation to a large T cell lymphoma (TR-MF), and 7 cases with folliculotropic variant (F-MF), were studied. Twenty cases showed genomic alterations (GAs): 8 (40 %) had CDKN2A deletion, 7 (35 %) showed MYC gain, and 5 (25 %) exhibited both alterations. GAs were more frequently observed in F-MF (p = 0.004) and TR-MF (p = 0.0001) than T-MF. GAs were significantly higher in cases presenting lesions in head, neck, and lower extremities compared to those observed in trunk and upper extremities (p = 0.03), when ≥25 % neoplastic cells were CD30 positive (p = 0.016) as well as in cases with higher Ki-67 proliferation index (p = 0.003). Patients with GAs showed bad response to treatment (p = 0.02) and short survival (p = 0.04). Furthermore, MF patients showed higher miRNA expression compared to controls (p ≤ 0.0223). T-MF showed higher miR17 and miR-18a expression compared to F-MF and TR-MF (p ≤ 0.0387) while miR19b, miR92a, and miR-155 showed increased levels in F-MF and TR-MF with respect to T-MF (p ≤ 0.0360). Increased expression of miR17 and miR19b in GA group compared to cases without alterations (p ≥ 0.0307) was also detected. Our results add new information about genomic imbalances in MF patients, particularly in F-MF, and extend the present view of miRNA deregulation in this disease.

Liu D, Tian Y, Sun D, et al.
The FCGR3A polymorphism predicts the response to rituximab-based therapy in patients with non-Hodgkin lymphoma: a meta-analysis.
Ann Hematol. 2016; 95(9):1483-90 [PubMed] Related Publications
Epidemiological studies have assessed the association between Fc gamma receptor IIIA (FCGR3A) 158 V/F and the response to rituximab-based therapy in patients with non-Hodgkin lymphoma (NHL), but the findings have been inconsistent. We performed this meta-analysis to obtain a better assessment of this relationship. Electronic database searches were conducted for relevant studies. A pooled odds ratio (OR) with a 95 % confidence interval (95 % CI) was used to assess the strength of the association. Analyses of the subgroup and publication bias were conducted. A total of 10 studies involving 1050 patients were analyzed. In all the genetic models, no clear relationship was found between the FCGR3A 158 V/F polymorphism and the response to rituximab-based therapy in NHL patients. When categorized by ethnicity, Asian individuals with the FCGR3A 158 V/V allele (OR = 4.37; 95 % CI = 1.07-17.73; P = 0.039) or the non-F/(FV + VV) (OR = 2.50; 95 % CI = 1.04-5.98; P = 0.040) allele have a significantly higher complete response rate (CR) compared to FF individuals. No obvious heterogeneities were observed. In addition, no statistical evidence for a publication bias was found. Our study suggested that the FCGR3A 158 V/F polymorphism can predict the treatment response to rituximab-based chemotherapy in NHL patients, especially for Asian individuals.

Yi B, Pei Y, Wang C, Jiang Y
[Association between cytotoxic T lymphocyte protein-4 polymorphisms and non-Hodgkin's lymphoma risk: a meta-analysis].
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2016; 32(8):1099-104 [PubMed] Related Publications
Objective To investigate the potential association of cytotoxic T lymphocyte associated protein 4 (CTLA4) polymorphisms with non-Hodgkin's lymphoma (NHL) risk. Methods Two reviewers independently searched the PubMed, MEDLINE, China National Knowledge Infrastructure (CNKI), Chinese WanFang databases and Database of Chinese Scientific and Technical Periodicals (VIP) for relevant studies from January 1, 1990 to May 25, 2016. Odds ratios (OR) with 95% confidence intervals (CI) for CTLA4 polymorphism and HNL risk were used to evaluate the strength of association. Meta-analysis was performed using SATA (v12.0) software. Results A total of 6 case-control studies concerning the CTLA4 +49A/G, -318T/C, and CT60A/G polymorphisms were included in the meta-analysis. The polymorphisms of the three alleles were not associated with genetic susceptibility to NHL (PZ>0.05 or 95%CI contains 1). In the subgroup analysis of CTLA4 +49A/G gene polymorphism, we found that AA was a risk factor for mixed type lymphoma (AA vs GG: OR=4.181, 95%CI: 1.362-12.833; AA+AG vs GG: OR=3.217, 95%CI: 1.055-9.810; AA vs AG+GG: OR=2.827, 95%CI: 1.345-5.940), but was a protect factor for B cell lymphoma (AA vs GG: OR=0.465, 95%CI: 0.251-0.863; AA vs AG+GG: OR=0.534, 95%CI: 0.362-0.788); AA was a risk factor in Italians (AA vs GG: OR=4.181, 95%CI: 1.362-12.833; AA+AG vs GG: OR=3.217, 95%CI: 1.055-9.810; AA vs AG+GG: OR=2.827, 95%CI: 1.345-5.940), but was a protect factor in Chinese (AA vs GG: OR=0.643, 95%CI: 0.417-0.992; AA vs AG+GG, OR=0.601, 95%CI: 0.395-0.913). Conclusion This meta-analysis suggests that the polymorphisms of the three alleles are not associated with genetic susceptibility to NHL.

Testo N, Olson LC, Subramaniyam S, et al.
Primary Cutaneous Diffuse Large B-Cell Lymphoma With a MYC-IGH Rearrangement and Gain of BCL2: Expanding the Spectrum of MYC/BCL2 Double-Hit Lymphomas.
Am J Dermatopathol. 2016; 38(10):769-74 [PubMed] Related Publications
Aggressive extracutaneous B-cell lymphomas span the various stages of B-cell ontogeny and include B-cell lymphoblastic lymphoma, Burkitt lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma. Diffuse large B-cell lymphomas represent the most common histologic subtype of non-Hodgkin lymphomas, comprising 30% of adult non-Hodgkin lymphomas in the United States. A distinctive form of diffuse large B-cell lymphoma is the double-hit lymphoma, with most cases exhibiting a combined MYC and BCL2 rearrangement, leading some hematopathologists to propose the term MYC/BCL2 lymphoma. More recently, MYC rearrangement with multiple copies/gain of BCL2 or multiple copies/gain of MYC with a BCL2 rearrangement have been described and exhibit a very similar clinical course to conventional double-hit lymphomas. We report the seventh case of diffuse large B-cell lymphoma exhibiting this distinct cytogenetic abnormality and the first reported case in the skin. The patient's clinical course was aggressive, succumbing to disease 18 months after his initial presentation.

Burkhardt B, Yavuz D, Zimmermann M, et al.
Impact of Fc gamma-receptor polymorphisms on the response to rituximab treatment in children and adolescents with mature B cell lymphoma/leukemia.
Ann Hematol. 2016; 95(9):1503-12 [PubMed] Related Publications
Recent studies in adult lymphoma patients have indicated a correlation between polymorphisms of Fc gamma-receptors (FcγRs, encoded by the respective FCGR genes) and the response to rituximab treatment. In vitro, cells expressing FcγRIIIa-158V mediate antibody-dependent cellular cytotoxicity (ADCC) more efficiently than cells expressing FcγRIIIa-158F. The impact of the FCGR2A-131HR polymorphism is unclear. In this study, the FCGR polymorphisms FCGR3A-158VF and FCGR2A-131HR were analyzed in pediatric patients with mature aggressive B cell non-Hodgkin lymphoma/leukemia (B-NHL). Pediatric patients received a single dose of rituximab monotherapy. Response was evaluated on day 5 followed by standard chemotherapy for B-NHL. Among 105 evaluable patients, a response to rituximab was observed in 21 % of those homozygous for FcγRIIa-131RR (5/24) compared to 48 % of patients who were HH and HR FcγRIIa-131 allele carriers (18/34 and 21/47, respectively; p = 0.044). Among patients with the FCGR3A-158 polymorphism, those homozygous for the FF genotype had a significantly favorable rituximab response rate of 59 % (22/37) compared to 32 % in patients who were FcγRIIIa-158VV and FcγRIIIa-VF allele carriers (2/9 and 20/59, respectively; p = 0.022). A stringent phase II response evaluation of children and adolescents with B-NHL after one dose of rituximab monotherapy showed a significant association between the rituximab response rate and FCGR polymorphisms. These findings support the hypothesis that FCGR polymorphisms represent patient-specific parameters that influence the response to rituximab.

Kiaei A, Onsori H, Alijani A, et al.
Detection of t(8;14) c-myc/IgH gene rearrangement by long-distance polymerase chain reaction in patients with diffuse large B-cell lymphoma.
Hematol Oncol Stem Cell Ther. 2016; 9(4):141-146 [PubMed] Related Publications
OBJECTIVE/BACKGROUND: Specific chromosomal translocations are found in human leukemias and lymphomas. These translocations are closely related to particular histological and immunological phenotypes. In Burkitt's lymphoma, translocation t(8;14)(q24;q32), which involves the c-myc gene (8q24) and the immunoglobulin heavy-chain (IgH) locus (14q32), accounts for 90-95% of all chromosomal translocations. This translocation can be found in 2-5% of diffuse large B-cell lymphoma (DLBCL). Long-distance polymerase chain reaction (LD-PCR) assays, which can identify oncogene/Ig gene rearrangement, can detect these fusion genes. The objective of this study was to detect t(8;14) c-myc/IgH gene rearrangement by LD-PCR in patients with DLBCL.
METHODS: In this study, 54 DLBCL cases were tested by LD-PCR with specific primers. LD-PCR was used for two breakpoints in both the IgH gene (joining region and γ switch region) and the myc gene (Exons 2 and 3).
RESULTS: As much as 1.85% of the samples were positive for the γ constant region and Exon 2 of the myc gene.
CONCLUSION: LD-PCR can be used for the detection of t(8;14) c-myc/IgH gene rearrangement in patients with DLBCL.

Due H, Svendsen P, Bødker JS, et al.
miR-155 as a Biomarker in B-Cell Malignancies.
Biomed Res Int. 2016; 2016:9513037 [PubMed] Free Access to Full Article Related Publications
MicroRNAs have the potential to be useful biomarkers in the development of individualized treatment since they are easy to detect, are relatively stable during sample handling, and are important determinants of cellular processes controlling pathogenesis, progression, and response to treatment of several types of cancers including B-cell malignancies. miR-155 is an oncomiR with a crucial role in tumor initiation and development of several B-cell malignancies. The present review elucidates the potential of miR-155 as a diagnostic, prognostic, or predictive biomarker in B-cell malignancies using a systematic search strategy to identify relevant literature. miR-155 was upregulated in several malignancies compared to nonmalignant controls and overexpression of miR-155 was further associated with poor prognosis. Elevated expression of miR-155 shows potential as a diagnostic and prognostic biomarker in diffuse large B-cell lymphoma and chronic lymphocytic leukemia. Additionally, in vitro and in vivo studies suggest miR-155 as an efficient therapeutic target, supporting its oncogenic function. The use of inhibiting anti-miR structures indicates promising potential as novel anticancer therapeutics. Reports from 53 studies prove that miR-155 has the potential to be a molecular tool in personalized medicine.

Zhao HB, Zhang XF, Shi F, et al.
Comparison of the expression of human equilibrative nucleotide transporter 1 (hENT1) and ribonucleotide reductase subunit M1 (RRM1) genes in seven non-Hodgkin lymphoma cell lines.
Genet Mol Res. 2016; 15(2) [PubMed] Related Publications
We investigated the variability in the expression of human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase subunit M1 (RRM1) in non-Hodgkin lymphoma cell lines. hENT1 and RRM1 mRNA expression levels in natural killer (NK) cells and seven non-Hodgkin lymphoma cell lines (YTS, SNK-6, Jeko-1, ly-1, Raji, Karpas, and Jurket) were studied using reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) and the results were compared using the Student t-test. mRNA expression of hENT1 was detectable in YTS, SNK-6, Jeko-1, ly-1, Raji, Karpas, Jurket, and NK cells, which revealed variability in gene expression. There were significant differences in the mRNA expression values of hENT1 (P = 0.021) and RRM1 (P = 0.002) compared to those in NK cells. mRNA expression of both hENT1 and RRM1 was closely associated with non-Hodgkin lymphoma cell proliferation. Differential expression analysis of hENT1 and RRM1 in non-Hodgkin lymphoma cell lines may provide novel drug leads for precision medicine.

Todorovic Balint M, Jelicic J, Mihaljevic B, et al.
Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses.
Int J Mol Sci. 2016; 17(5) [PubMed] Free Access to Full Article Related Publications
The existence of a potential primary central nervous system lymphoma-specific genomic signature that differs from the systemic form of diffuse large B cell lymphoma (DLBCL) has been suggested, but is still controversial. We investigated 19 patients with primary DLBCL of central nervous system (DLBCL CNS) using the TruSeq Amplicon Cancer Panel (TSACP) for 48 cancer-related genes. Next generation sequencing (NGS) analyses have revealed that over 80% of potentially protein-changing mutations were located in eight genes (CTNNB1, PIK3CA, PTEN, ATM, KRAS, PTPN11, TP53 and JAK3), pointing to the potential role of these genes in lymphomagenesis. TP53 was the only gene harboring mutations in all 19 patients. In addition, the presence of mutated TP53 and ATM genes correlated with a higher total number of mutations in other analyzed genes. Furthermore, the presence of mutated ATM correlated with poorer event-free survival (EFS) (p = 0.036). The presence of the mutated SMO gene correlated with earlier disease relapse (p = 0.023), inferior event-free survival (p = 0.011) and overall survival (OS) (p = 0.017), while mutations in the PTEN gene were associated with inferior OS (p = 0.048). Our findings suggest that the TP53 and ATM genes could be involved in the molecular pathophysiology of primary DLBCL CNS, whereas mutations in the PTEN and SMO genes could affect survival regardless of the initial treatment approach.

Chen BY, Hu JD, Lin RZ, Chen XJ
[Knockout of Micro-RNA-21 Gene in DLBCL OCI-Ly3 cells by TALEN Technique].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2016; 24(2):422-6 [PubMed] Related Publications
OBJECTIVE: To explore an efficient way to knockout microRNA genes in hemapoietic cell lines with a very low transfection efficiency, so as to facilitate the study of microRNA function in hematopoietic malignancies.
METHODS: TALE-nucleases was utilized to knockout the microRNA-21 gene in human diffuse large B-cell lymphoma cells (OCI-Ly3). The OCI-Ly3 single cell clones without expression of miR-21 were established through eGFP(+) enrichment, PCR screening, and microRNA quantification. Finally, the miR-21 changes of mutant clones were identified by sequencing.
RESULTS: Four miR-21-knockouted OCI-Ly3 single-cell-derived clones were established after 2 round transfection and screening. The miR-21 knockout efficiency was around 10/10(6) original cells. Sequencing the mutant clones indicated that miR-21 expression could be drastically reduced by simply altering sequences immediately adjacent to the microRNA duplex.
CONCLUSION: This strategy may be applied to knockout any microRNA of interest even in hemapoietic cell lines with very low transfection efficiency.

Flinders C, Lam L, Rubbi L, et al.
Epigenetic changes mediated by polycomb repressive complex 2 and E2a are associated with drug resistance in a mouse model of lymphoma.
Genome Med. 2016; 8(1):54 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The genetic origins of chemotherapy resistance are well established; however, the role of epigenetics in drug resistance is less well understood. To investigate mechanisms of drug resistance, we performed systematic genetic, epigenetic, and transcriptomic analyses of an alkylating agent-sensitive murine lymphoma cell line and a series of resistant lines derived by drug dose escalation.
METHODS: Dose escalation of the alkylating agent mafosfamide was used to create a series of increasingly drug-resistant mouse Burkitt's lymphoma cell lines. Whole genome sequencing, DNA microarrays, reduced representation bisulfite sequencing, and chromatin immunoprecipitation sequencing were used to identify alterations in DNA sequence, mRNA expression, CpG methylation, and H3K27me3 occupancy, respectively, that were associated with increased resistance.
RESULTS: Our data suggest that acquired resistance cannot be explained by genetic alterations. Based on integration of transcriptional profiles with transcription factor binding data, we hypothesize that resistance is driven by epigenetic plasticity. We observed that the resistant cells had H3K27me3 and DNA methylation profiles distinct from those of the parental lines. Moreover, we observed DNA methylation changes in the promoters of genes regulated by E2a and members of the polycomb repressor complex 2 (PRC2) and differentially expressed genes were enriched for targets of E2a. The integrative analysis considering H3K27me3 further supported a role for PRC2 in mediating resistance. By integrating our results with data from the Immunological Genome Project (Immgen.org), we showed that these transcriptional changes track the B-cell maturation axis.
CONCLUSIONS: Our data suggest a novel mechanism of drug resistance in which E2a and PRC2 drive changes in the B-cell epigenome; these alterations attenuate alkylating agent treatment-induced apoptosis.

Campuzano-Zuluaga G, Ortiz D, Peng JH, et al.
Primary Mediastinal Large B-Cell Lymphoma With Translocations Involving BCL6 and MYC (Double-Hit Lymphoma).
Am J Clin Pathol. 2016; 145(5):710-6 [PubMed] Related Publications
OBJECTIVES: Primary mediastinal large B-cell lymphomas (PMLBCLs) are aggressive lymphomas with characteristic clinical, morphologic, and immunophenotypic features. "Double-hit" (DH) lymphomas are B-cell neoplasms characterized by a translocation involving MYC and either BCL2 or BCL6 In the indexed literature, there are no reported cases of PMLBCL associated with DH or triple-hit events.
METHODS: Herein, we present a case of a 15-year-old girl with PMLBCL who had typical clinical, morphologic, and immunophenotypic features.
RESULTS: Fluorescent in situ hybridization studies showed rearrangements involving MYC and BCL6 We also excluded the possibility of a reciprocal t(3;8) (3q27;8q24) BCL6/MYC translocation.
CONCLUSIONS: This case expands the current spectrum of lymphomas subtypes in which DH can be found and supports the rationale for cytogenetic testing for DH abnormalities in all cases of aggressive large B-cell lymphomas regardless of subtype.

Vasilatou D, Sioulas AD, Pappa V, et al.
The role of miRNAs and epigenetic mechanisms in primary gastric mucosa-associated lymphoid tissue lymphoma.
Future Oncol. 2016; 12(13):1587-93 [PubMed] Related Publications
Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a rare low-grade B-cell non-Hodgkin lymphoma associated with Helicobacter pylori infection and the subsequent chronic inflammation. Significant progress in understanding the pathogenesis of the disease has already been made. However, the exact molecular pathways of lymphomagenesis remain unclear. Furthermore, difficulties regarding accurate diagnosis of gastric MALT lymphoma and its discrimination from gastritis or other lymphoma subtypes arise. Recent studies evaluate the role of miRNAs and epigenetic alterations on MALT lymphoma pathogenesis and prognosis. This review critically summarizes the most important data on the role of miRNAs and epigenetics in MALT lymphomas pathogenesis, prognosis and treatment.

Peng W, Wu J, Feng J
Long noncoding RNA HULC predicts poor clinical outcome and represents pro-oncogenic activity in diffuse large B-cell lymphoma.
Biomed Pharmacother. 2016; 79:188-93 [PubMed] Related Publications
Diffuse large B-cell lymphoma (DLBCL) is one of the leading causes of cancer-related mortality, and responds badly to existing treatment. Thus, it is of urgent need to identify novel prognostic markers and therapeutic targets of DLBCL. Emerging studies have implicated that long noncoding RNAs (lncRNAs) are differentially expressed in various tumors and play an important role in the development of cancer. Previously, our group has reported that the novel lncRNA HULC has important biological function and clinical potential in human pancreatic cancer. Here, we investigated the expression of HULC in a cohort of DLBCL to assess its expression pattern, clinical value and molecular mechanism. Firstly, we found that HULC was remarkably overexpressed in both DLBCL tissues and cell lines. Moreover, we illustrated that HULC was closely related to DLBCL characteristics, such as Ann Arbor stages, B symptoms, CHOP-like treatment, rituximab and IPI. Importantly, we verified that HULC was an key predictive factor for DLBCL diagnosis and prognosis from sizable samples through the long time follow-ups. Furthermore, we reveal that the HULC knockdown could significantly arrest cell proliferation and induce apoptosis by repressing cyclin D1 and Bcl-2 in DLBCL cells. Our results suggested that HULC could represent a novel indicator of poor prognosis and may be served as a potential target for the diagnosis and gene therapy of DLBCL.

Robaina MC, Faccion RS, Mazzoccoli L, et al.
miR-17-92 cluster components analysis in Burkitt lymphoma: overexpression of miR-17 is associated with poor prognosis.
Ann Hematol. 2016; 95(6):881-91 [PubMed] Related Publications
Burkitt lymphoma (BL) is an aggressive B cell lymphoma characterized by the reciprocal translocation of the c-Myc gene with immunoglobulin genes. Recently, MYC has been shown to maintain the neoplastic state via the miR-17-92 microRNA cluster that suppresses chromatin regulatory genes and the apoptosis regulator Bim. However, the expression and prognostic impact of miR-17-92 members in pediatric BL (pBL) are unknown. Therefore, we investigated miR-17, miR-19a, miR-19b, miR-20, and miR-92a expression and prognostic impact in a series of 41 pBL samples. In addition, Bim protein expression was evaluated and compared to miR-17, miR-19a, miR-19b, miR-20, and miR-92a levels and patient outcomes. The expression of miR-17-92 members was evaluated by qPCR and Bim protein by immunohistochemistry. Log-rank test was employed to assess prognostic impact. We found that upregulated expression of miR-17 and miR-20a correlates with lack of pro-apoptotic Bim expression. Patients bearing tumors with upregulated miR-17 displayed decreased overall survival (OS), and multivariate analysis revealed that miR-17 was a significant predictor of shortened OS. Using hairpin inhibitors, we showed that inhibition of miR-17 resulted in enhanced Bim expression in a BL cell line overexpressing the miR-17-92 cluster. Our results describe for the first time miR-17, miR-19a, miR-19b, miR-20a, and miR-92a expression profiles in pBL. The prognostic impact of miR-17 should be validated in a larger series, and may provide new therapeutic avenues in the era of anti-miRNA therapy research. Additional functional studies are further required to understand the specific role of miR-17-92 cluster members in BL.

Kawamoto K, Miyoshi H, Yoshida N, et al.
MYC translocation and/or BCL 2 protein expression are associated with poor prognosis in diffuse large B-cell lymphoma.
Cancer Sci. 2016; 107(6):853-61 [PubMed] Free Access to Full Article Related Publications
Genomic alterations and protein expression levels have been established as prognostic factors for survival in patients with diffuse large B-cell lymphoma (DLBCL). In particular, double-hit DLBCL (DHL), which exhibits translocations in MYC and BCL2 and/or BCL6, is known to be associated with a poor prognosis. However, the clinical significance of gene alterations and protein expression levels for MYC, B-cell lymphoma (BCL)2, and BCL6 are unclear. In this study, we analyzed 61 adult patients diagnosed with DLBCL without DHL, who were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone, or similar regimens. There were no differences in the distribution of MYC expression rates among the different MYC gene statuses. In log-rank tests, MYC translocation was a prognostic factor for overall survival (OS; P = 0.011), whereas BCL2 and BCL6 translocation were not prognostic indicators (P = 0.999 and P = 0.925, respectively). Although the expression levels of MYC and BCL6 were not significantly associated with OS, the expression of BCL2 was a prognostic factor for OS (P = 0.027). Furthermore, copy number gains in the MYC, BCL2, and BCL6 genes did not affect OS. MYC translocation (hazard ratio, 4.769; range, 1.518-14.98; P = 0.007) and BCL2 protein expression (hazard ratio, 3.072; range, 1.002-9.413; P = 0.049) were independent prognostic factors for survival in multivariate analyses. In conclusion, MYC translocation and BCL2 expression may need to be investigated at the initial diagnosis to predict prognosis in patients with DLBCL.

Masamha CP, Albrecht TR, Wagner EJ
Discovery and characterization of a novel CCND1/MRCK gene fusion in mantle cell lymphoma.
J Hematol Oncol. 2016; 9:30 [PubMed] Free Access to Full Article Related Publications
The t(11;14) translocation resulting in constitutive cyclin D1 expression is an early event in mantle cell lymphoma (MCL) transformation. Patients with a highly proliferative phenotype produce cyclin D1 transcripts with truncated 3'UTRs that evade miRNA regulation. Here, we report the recurrence of a novel gene fusion in MCL cell lines and MCL patient isolates that consists of the full protein coding region of cyclin D1 (CCND1) and a 3'UTR consisting of sequences from both the CCND1 3'UTR and myotonic dystrophy kinase-related Cdc42-binding kinase's (MRCK) intron one. The resulting CCND1/MRCK mRNA is resistant to CCND1-targeted miRNA regulation, and targeting the MRCK region of the chimeric 3'UTR with siRNA results in decreased CCND1 levels.

Pagano JS, Shackelford J
UCH-L1 in DLBCL: marker or target?
Blood. 2016; 127(12):1524-5 [PubMed] Related Publications
In this issue of Blood, Bedekovics et al have demonstrated that a multifunctional molecule of the ubiquitin system ubiquitin C-terminal hydrolase L1 (UCH-L1) is induced in diffuse large B-cell lymphomas (DLBCLs), and that levels of this molecule are higher in germinal center (GC) B-cell DLBCL (GCB-DLBCL) compared with activated B-cell DLBCL (ABC-DLBCL) and predict poor outcomes.

Recurrent Structural Alterations

Selected list of common recurrent structural abnormalities

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

t(8;14;12)(q24.1;q32.3;q24.1) in a Burkitt's lymphoma

add(14q32) / dup(14p32) in Non-Hodgkin's Lymphoma

Arcaroli JJ, Dave BJ, Pickering DL, et al.
Is a duplication of 14q32 a new recurrent chromosomal alteration in B-cell non-Hodgkin lymphoma?
Cancer Genet Cytogenet. 1999; 113(1):19-24 [PubMed] Related Publications
Identification of clonal chromosomal abnormalities involving 14q32 and its association with specific histological subtypes of non-Hodgkin lymphoma (NHL) has provided substantial insight to the genetic events leading to the disease. However, in some cases with inferior morphology of tumor cell chromosomes, the additional segment on chromosome 14 remains unidentified by cytogenetic banding techniques alone. To elucidate the origin of the additional chromosomal segment and to correlate the newly determined alterations with histology, metaphases from 15 NHL patients with add(14)(q32) were examined using fluorescence in situ hybridization (FISH) techniques after cytogenetic analysis had been performed. We found the duplication of 14q involving the q32 region in 6 cases with a dup(14) (q32) in 4 cases and a dup(14)(q24q32) in 2 cases. In 8 cases, FISH unveiled known NHL associated translocations; a t(14;18)(q32;q21) in 4 cases, a t(11;14)(q13;q32) in 2 cases, a t(8;14)(q24;q32) and a t(9;14)(p13;q32) in 1 case each. We also noted a t(14;17)(q32;q21) in 1 case. The use of FISH was a valuable asset in determining the origin of the additional material on chromosome 14q32, and helped resolve a group of B-cell NHLs with involvement of a duplicated 14q32 region.

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