Specific Lymphoma Subtypes Research Articles

Cerebrospinal fluid approach on neuro-oncology

Central nervous system (CNS) involvement is a major complication of haematological and solid tumors with an incidence that ranges from 10% in solid malignancies up to 25% in specific leukaemia or lymphoma subtypes. Cerebrospinal fluid (CSF) patterns are unspecific. Though CSF cytology has a high specificity (up to 95%), its sensitivity is generally less than 50% and no diagnostic gold standard marker is available, yet. New technologies such as flow cytometry, molecular genetics and newer biomarkers may improve diagnostic sensitivity and specificity, leading to the CNS involvement diagnosis, and consequently, to an effective prophylaxis and successful treatment.

Gene Expression Profiling of Non-Hodgkin Lymphomas

Chromosomal translocations are genetic aberrations associated with specific non-Hodgkin lymphoma (NHL) subtypes. This study investigated the differential gene expression profile of Egyptian NHL cases based on a microarray approach. The study included tissue samples from 40 NHL patients and 20 normal lymph nodes used as controls. Total RNA was extracted and used for cDNA microarray assays. The quantitative real time polymerase chain reaction was used to identify the aberrantly expressed genes in cancer. Significant associations of 8 up-regulated and 4 down-regulated genes with NHL were observed. Aberrant expression of a new group of genes not reported previously was apparent, including down-regulated NAG14 protein, 3 beta hydroxy-delta 5-c27 steroid oxi-reductase, oxi-glutarate dehydrogenase (lipo-amide), immunoglobulin lambda like polypeptide 3, protein kinase x linked, Hmt1, and caveolin 2 Tetra protein. The up-regulated genes were Rb binding protein 5, DKFZP586J1624 protein, protein kinase inhibitor gamma, zinc finger protein 3, choline ethanolamine phospho-transferase CEPT1, protein phosphatase, and histone deacetylase-3. This study revealed that new differentially expressed genes that may be markers for NHL patients and individuals who are at high risk for cancer development.

Successive B-Cell Lymphomas Mostly Reflect Recurrences Rather Than Unrelated Primary Lymphomas

To address whether successive B-cell lymphomas, diagnosed within a 5- to 15-year interval, are recurrences or unrelated primary lymphomas. Immunoglobulin heavy and κ light chain gene rearrangements were studied using multiplex polymerase chain reaction fragment assays and sequence analysis in 61 patients. Clonal patterns of the multiple lymphomas from 36 patients were determined and classified accordingly: 30 recurrences, 2 possible recurrences, 2 different clones with a common origin, and 2 unrelated primary lymphomas. Regardless of subtype, 89% to 94% of late B-cell lymphoma relapses were recurrences of the primary tumor. Therefore, routinely investigating the possible clonal relationship between successive lymphomas may not be warranted except for specific lymphoma subtypes such as diffuse large B-cell lymphomas.

„In-situ-Lymphome“ und andere Frühstadien maligner Non-Hodgkin-Lymphome

The increasing use of immunohistochemical and molecular investigations of lymphatic tissues results in more frequent detection of early lymphoid proliferations. These show some but not all features of malignant lymphomas without fulfilling the diagnostic criteria for the diagnosis of lymphoid malignancy. In addition to well-known premalignant B-cell proliferations, such as monoclonal gammopathy of unknown significance (MGUS) and monoclonal B-cell lymphocytosis (MBL), so-called in situ lymphomas have recently been described with minimal infiltrates of clonal B-cells in morphologically reactive lymphoid tissues which show the phenotypic and genetic features of specific B-cell lymphoma subtypes and often show a characteristic topographical distribution. This article addresses a group of clonal lymphoproliferations with usually localized disease and excellent clinical prognosis, such as pediatric follicular lymphoma and nodal marginal zone lymphoma. Another group of early lesions not addressed in this review are virally induced lymphoproliferations which represent a grey zone between purely reactive lesions and malignant lymphomas and may pose significant diagnostic as well as clinical problems. In this review diagnostic criteria for early or in situ lesions and their distinction from partial infiltration by malignant lymphoma are described.

Dual Targeting of Protein Degradation Pathways with the Selective HDAC6 Inhibitor Rocilinostat (ACY-1215) and Bortezomib, Demonstrates Synergistic Antitumor Activity in Preclinical Models of Lymphoma

AbstractAbstract 1650The emergence of epigenetic therapies has identified histone deacetylase(HDAC) inhibitors as effective therapeutic agents for the treatment of refractory lymphoma. While pan-class I/II HDAC inhibitors have led to treatment ramifications, recently goals have shifted to the development of discrete HDAC selective inhibitors to further define and better target pathways germane to specific subtypes of lymphoma. We investigated the therapeutic impact of the selective HDAC6 inhibitor rocilinostat (ACY-1215) (Acetylon Pharmaceuticals, Inc) in a panoply of lymphoma cell lines. HDAC6, a class IIb histone deacetylase, binds polyubiquinated, misfolded protein aggregates and facilitates their transport to the aggresome. The aggresome then sequesters these aggregates for degradation. The aggresomal pathway is proteasome-independent and is a key outlet for the unfolded protein response (UPR). The purpose of this study was to determine whether inhibition of HDAC6 with rocilinostat leads to an accumulation of misfolded proteins, activates the UPR stress response and ultimately induces apoptosis. These results have been confirmed in preclinical models of multiple myeloma, and the drug is currently being evaluated in clinical trials for that disease [1]. We evaluated the single agent activity of rocilinostat, its synergistic potential when combined with bortezomib, and the mechanism of action of this combination in lymphoma with respect to inhibiting two separate protein degradation pathways.Single agent dose-effect curves were generated for 8 diffuse large B-cell lymphoma (DLBCL) cell lines (4 germinal-center type: OCI-Ly1, OCI-Ly7, Su-DHL4, Su-HDL6; 4 activated B-cell type: OCI-Ly10, Su-DHL2, HBL-1, RIVA), 4 mantle cell lymphoma (MCL) cell lines (Maver, JVM-1, JEKO, Rec-1), and 2 T-cell lymphoma cell lines (HH and H9). The inhibitory concentration 50% (IC50) values were calculated after exposure for 24, 48, and 72 hours. Maximal cytotoxicity was observed in all cell lines at 48–72 hours with IC50 values ranging between 240–3500 nM. Activity was greatest in the cell lines OCI-Ly10 and OCI-Ly7, with 72-hour IC50 values of 240 nM and 255 nM respectively. Rocinlinostat began to show irreversible activity after 6 hours of exposure. The cytotoxicity of rocilinostat in combination with bortezomib was measured and evaluated for schedule and dose dependency in OCI-Ly10. The greatest synergy was observed with simultaneous exposure and was first established at the concentrations rocilinostat750 nM and bortezomib 3 nM (CI=0.576). Synergy did not depend on the concentration of one drug over the other. Eight additional cells lines were evaluated for synergy with similar results. Cell death occurred by apoptosis as evaluated through FACS analysis for annexin V/propidium iodide, and cleavage of caspase 3 and PARP by immunoblotting. Treatment of OCI-Ly10 and Su-DHL6 cells with rocilinostat led to acetylation of a-tubulin, increased poly-ubiquitinated proteins, PERK, GRP78, p-eIF2a, and spliced XBP-1 as detected by immunoblotting. These effects were enhanced by treatment with bortezomib, and confirm that accumulation of misfolded proteins activates the UPR response triggering apoptosis, and substantiates blocking two protein degradation systems simultaneously. In addition, p65 NF#x2610;#x0025;B subunit was decreased with the combination. Slight acetylation of H3 was observed following treatment with roclinostat, but this was considerably less compared with cells treated with pan-Class I/II HDAC inhibitors and confirms selectivity of the drug.These are the first results to indicate that a selective HDAC inhibitor can have marked activity across a panel of lymphoma cell lines. Future studies will evaluate efficacy and tolerability in in vivo models of lymphoma, and further define mechanism of action. Taken together, these findings raise the prospect that dual targeting of the ubiquitin-proteasome and aggressomal protein degradation pathways can be synergistically effective and provide excellent pre-clinical rationale for expanding the use of rocilinostat in combination with bortezomib for patients with relapsed or refractory lymphoma. [Display omitted] Disclosures:Amengual:Acetylon Pharmaceuticals, Inc: Research Funding. Jones:Acetylon Pharmaceuticals, Inc: Employment. O'Connor:Millenium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics, Inc: Consultancy; Seattle Genetics, Inc: Membership on an entity's Board of Directors or advisory committees; Allos Therapeutics, Inc: Consultancy.

Lymphoma risk and occupational exposure to pesticides: results of the Epilymph study

ObjectivesWe investigated the role of occupational exposure to specific groups of agrochemicals in the aetiology of lymphoma overall, B cell lymphoma and its most prevalent subtypes.MethodsIn 1998–2003, 2348 incident lymphoma...

Lymphoma risk and occupational exposure to pesticides: results of the EPILYMPH study

ObjectivesSeveral agricultural pesticides have shown a carcinogenic potential in experimental animals.MethodsIn 1998–2003, 2337 incident lymphoma cases and 2434 controls participated in the EPILYMPH case-control study in six European countries. A...

Risk of specific lymphoma subtypes is associated to polymorphism in genes implicated in the metabolism of workplace carcinogens

ObjectivesExploring lymphoma risk associated with metabolic gene polymorphisms might provide clues on the role of gene-environment interactions in lymphomagenesis.MethodsWe assessed polymorphisms in genes encoding for the metabolic enzymes CYP1A2, CYP2E1,...

Lymphoma risk among animal breeders

ObjectivesOccupational contact with breeding animals might be implicated in lymphoma aetiology.MethodsIn 1998–2003, 2337 incident lymphoma cases and 2434 controls participated in the EPILYMPH case-control study in six European countries. A...

Nuclei micro-array FISH, a desirable alternative for MCL diagnosis

Mantle cell lymphoma (MCL) is a rare, specific lymphoma subtype. Though the morphologic and immunophenotypic features of MCL have been well described in recent literatures, it is still a diagnostic dilemma because of its frequent confusion with other small B cell lymphomas (SBCLs). In the present study, we primarily focus on establishing a sensitive and specific method for the diagnosis of MCL, which is efficient to distinguish this disease from other SBCLs. We carried out our investigation for MCL and other SBCLs (including SLL, FL, MZL, and MALT) on their feature of morphology, immunophenotype, and t(11;14)(q13;q32) translocation analysis based on polymerase chain reaction (PCR) and interphase nuclei micro-array fluorescence in situ hybridization (FISH). The morphologic and immunologic analysis showed the positive rate of cyclin D1 was 76.47% in MCL, which was significantly higher than that in other SBCLs. The positive rate of t(11;14) translocation was 25.81% and 35.48%, respectively, tested by general and semi-nested PCR, while 93.10% positive rate was shown with low background and strong signals pattern when tested by Nuclei micro-array FISH. Our research shows that t(11;14) translocation is a special and useful diagnostic marker for MCL, and detection of the marker by nuclei micro-array FISH is convenient and economic, especially more sensitive and specific than other methods for the diagnosis of MCL.

Epigenetic regulation of CD44in Hodgkin and non-Hodgkin lymphoma

BackgroundEpigenetic inactivation of tumor suppressor genes (TSG) by promoter CpG island hypermethylation is a hallmark of cancer. To assay its extent in human lymphoma, methylation of 24 TSG was analyzed in lymphoma-derived cell lines as well as in patient samples.MethodsWe screened for TSG methylation using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in 40 lymphoma-derived cell lines representing anaplastic large cell lymphoma, Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Hodgkin lymphoma and mantle cell lymphoma (MCL) as well as in 50 primary lymphoma samples. The methylation status of differentially methylated CD44 was verified by methylation-specific PCR and bisulfite sequencing. Gene expression of CD44 and its reactivation by DNA demethylation was determined by quantitative real-time PCR and on the protein level by flow cytometry. Induction of apoptosis by anti-CD44 antibody was analyzed by annexin-V/PI staining and flow cytometry.ResultsOn average 8 ± 2.8 of 24 TSG were methylated per lymphoma cell line and 2.4 ± 2 of 24 TSG in primary lymphomas, whereas 0/24 TSG were methylated in tonsils and blood mononuclear cells from healthy donors. Notably, we identified that CD44 was hypermethylated and transcriptionally silenced in all BL and most FL and DLBCL cell lines, but was usually unmethylated and expressed in MCL cell lines. Concordant results were obtained from primary lymphoma material: CD44 was not methylated in MCL patients (0/11) whereas CD44 was frequently hypermethylated in BL patients (18/29). In cell lines with CD44 hypermethylation, expression was re-inducible at mRNA and protein levels by treatment with the DNA demethylating agent 5-Aza-2'-deoxycytidine, confirming epigenetic regulation of CD44. CD44 ligation assays with a monoclonal anti-CD44 antibody showed that CD44 can mediate apoptosis in CD44+ lymphoma cells. CD44 hypermethylated, CD44- lymphoma cell lines were consistently resistant towards anti-CD44 induced apoptosis.ConclusionOur data show that CD44 is epigenetically regulated in lymphoma and undergoes de novo methylation in distinct lymphoma subtypes like BL. Thus CD44 may be a promising new epigenetic marker for diagnosis and a potential therapeutic target for the treatment of specific lymphoma subtypes.

Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for the Evaluation of Suspected Lymphoma

Evidence regarding the utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the assessment of isolated mediastinal lymphadenopathy (IMLN) is evolving. Its diagnostic accuracy in the evaluation of suspected lymphoma remains uncertain. We reviewed a prospectively recorded database of consecutive patients with suspected lymphoma who underwent EBUSTBNA to evaluate IMLN. Patients in whom EBUS-TBNA was nondiagnostic subsequently underwent surgical biopsy or a minimum of 6 months radiologic surveillance. Ninety-eight patients underwent EBUS-TBNA for evaluation of IMLN. Clinicoradiologic features suggested sarcoidosis as the likely diagnosis in 43 patients. In the remaining 55 patients, EBUS-TBNA achieved definitive diagnosis in 42 patients (76%; 95% confidence interval [CI] 55-90). Lymphoma was ultimately diagnosed in 21 of 55 patients (38%). EBUS-TBNA demonstrated lymphoma in 16 (76%) patients; however, four patients required further surgical biopsy to completely characterize lymphoma subtypes. Surgical biopsy was required to diagnose specific lymphoma subtypes not readily amenable to diagnosis with low volume specimens. Sensitivity and specificity for definitive diagnosis of lymphoma were 57% (95% CI 37-76) and 100% (95% CI 91-100), respectively. Although the diagnostic accuracy of EBUS-TBNA for lymphoma is lower than that for the lung cancer staging, the procedure is an appropriate investigative technique for the patients with IMLN because of the low incidence of lymphoma in this population, and the significant proportion of such patients (76%) in whom surgical biopsy is obviated.

Anaplastic plasmacytoma of mouse—establishing parallels between subtypes of mouse and human plasma cell neoplasia

Mouse models may provide an important tool for basic and applied research on human diseases. An ideal tumour model should replicate the phenotypic and molecular characteristics of human malignancy as well as the typical physiological effects and dissemination patterns. The histopathological and molecular genetic characterization of anaplastic plasmacytoma (APCT) in strain NSF.V(+) mice provides an example to achieve this goal for a specific lymphoma subtype. Firstly, it demonstrates that, like plasma-cell neoplasms in humans, those in mice occur as distinct subtypes. Secondly, it shows that mouse APCT exhibits striking parallels to possible human tumour counterparts for which good mouse models of de novo tumour development are sorely needed: IgM(+) multiple myeloma and Waldenström's macroglobulinaemia. Thirdly, it strongly suggests that insertional somatic mutagenesis, by either a murine leukaemia virus or an oncogenic transposon, would be an effective experimental approach to accelerating malignant transformation of mature B cells and plasma cells in mice and, thereby, tagging and uncovering cancer driver genes that may be of great relevance for the tumour initiation and progression in lymphoma.

Increased Risk for Lymphoid and Myeloid Neoplasms in Elderly Solid-Organ Transplant Recipients

By assessing the spectrum of hematologic malignancies associated with solid-organ transplantation in the elderly, we provide information on the pathogenesis of lymphoid and myeloid neoplasms and the clinical manifestations of immunosuppression. Using data from the U.S. Surveillance, Epidemiology, and End Results Medicare database, we identified 83,016 cases with a hematologic malignancy (age 66-99 years) and 166,057 population-based controls matched to cases by age, sex, and calendar year. Medicare claims were used to identify a history of solid-organ transplantation. We used polytomous logistic regression to calculate odds ratios (OR) comparing transplantation history among cases with various hematologic malignancy subtypes and controls, adjusting for the matching factors and race. A prior solid-organ transplant was identified in 216 (0.26%) cases and 204 (0.12%) controls. Transplantation was associated with increased risk for non-Hodgkin lymphomas [OR, 2.13; 95% confidence interval (95% CI), 1.67-2.72], especially diffuse large B-cell lymphoma (OR, 3.29; 95% CI, 2.28-4.76), marginal zone lymphoma (OR, 2.48; 95% CI, 1.17-5.22), lymphoplasmacytic lymphoma (OR, 3.32; 95% CI, 1.41-7.81), and T-cell lymphoma (OR, 3.07; 95% CI, 1.56-6.06). Transplantation was also associated with elevated risk of Hodgkin lymphoma (OR, 2.53; 95% CI, 1.01-6.35) and plasma cell neoplasms (OR, 1.91; 95% CI, 1.24-2.93). Risks for myeloid neoplasms were also elevated (OR, 1.99; 95% CI, 1.41-2.81). Solid-organ transplantation is associated with a wide spectrum of hematologic malignancies in the elderly. Risk was increased for four specific non-Hodgkin lymphoma subtypes for which a viral agent has been implicated, supporting an added role for immunosuppression. Our results support monitoring for a wide spectrum of hematologic malignancies following solid-organ transplant.

Abstract 5740: Alcoholic beverage consumption and the incidence of non-Hodgkin lymphoma in the Cancer Prevention Study-II (CPS-II) Nutrition Cohort

Abstract Results of several case-control studies suggest an inverse association between alcohol consumption and risk of NHL, and potential differences in the strength of association across histologic subtypes. However, this relationship has been examined in few prospective cohort studies and of these, two included only women. Furthermore, most cohort studies had too few cases to explore potential differences in association according to histologic subtypes, gender and other factors. Using data from the large American Cancer Society CPS-II Nutrition Cohort, we examined the association of self-reported alcohol intake with the incidence of NHL in men and in women, and in ever and never smokers. We also examined associations according to specific NHL subtypes. Among the 70,424 men and 78,019 women included in this analysis, 1,120 male and 865 female incident cases of lymphoma were identified during the follow-up period (1992-2007). Multivariable-adjusted relative risks (RR) and 95% confidence intervals (CI) were computed using Cox proportional hazards regression controlling for age, race/ethnicity, smoking status, family history of hematopoietic cancer, education, body mass index, height and physical activity (METS). For men, the RR (95% CI) estimates for all NHL subtypes combined associated with consumption of >0-<1, 1-2, and >2 drinks per day compared to non-drinkers were 0.94 (0.82-1.08), 0.90 (0.74-1.08), and 0.80 (0.66-0.98) (p-trend=0.04). The corresponding RR (95% CI) estimates were similar for women (i.e., 0.92 (0.80-1.07), 0.87 (0.66-1.15) and 0.68 (0.47-0.99) (p-trend=0.04)). There was no effect modification of this association by gender (p for interaction=0.93). In addition, there was no effect modification by smoking status (p for interaction=0.76). In analyses of specific NHL subtypes, a statistically significant inverse association was observed for B-cell lymphomas, which comprised the majority of NHL neoplasms (i.e., >90%). For men and women combined, the RRs (95% CIs) for B-cell lymphoma associated with consumption of >0-<1, 1-2, and >2 drinks per day compared to non-drinkers were 0.96 (0.86-1.06), 0.91 (0.77-1.07) and 0.76 (0.64-0.92) (p-trend=0.004). However, we also observed non-significant inverse associations of alcohol intake with nearly all NHL subtypes. In summary, results from this large prospective cohort study support previous reports from other studies showing an inverse association between alcohol intake and the incidence of lymphoma in men and in women. They also suggest no meaningful differences in the nature of the association of alcohol intake with the incidence of specific histologic subtypes of lymphoma, or by smoking status. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5740.

T-cell/histiocyte-rich large B-cell lymphoma

T-cell/histiocyte-rich large B-cell lymphoma (THRLB-CL) can be used as a paradigm to highlight the difficulties in defining specific subtypes of diffuse large B-cell lymphoma. Since the first recognition of certain large B-cell lymphomas in which the tumor cell content was dramatically outnumbered

Characterization of D-cyclin proteins in hematolymphoid neoplasms: lack of specificity of cyclin-D2 and D3 expression in lymphoma subtypes

D-cyclin proteins play a central role in cell-cycle regulation and are involved in the pathogenesis of lymphomas. In mantle-cell lymphoma, the t(11;14) translocation leads to overexpression of cyclin-D1, in addition to which cyclin-D1-negative mantle-cell lymphoma that overexpress cyclin-D2 or D3 have also been described. Although cyclin-D2 and D3 have been implicated in the prognosis of specific lymphoma subtypes, a thorough characterization of D-cyclin protein expression in human hematolymphoid neoplasia has not been reported. To evaluate the tissue expression patterns of D-cyclins, particularly D2 and D3, in normal and neoplastic hematolymphoid tissues, we optimized the commercially available antibodies for D-cyclins for use on paraffin-embedded tissue and stained tissue microarrays of over 700 patient samples. Our results show that cyclin-D2 and D3 proteins are expressed in many more lymphoma subtypes than cyclin-D1. Cyclin-D1, D2 and D3 were expressed in 100, 22 and 6% of mantle-cell lymphomas and 2, 49 and 20% of diffuse large B-cell lymphomas. Fluorescence in situ hybridization studies confirmed the presence of the CCND1/IGH translocation in the majority of mantle-cell lymphoma, but not in diffuse large B-cell lymphoma that expressed cyclin-D1 protein. In addition, a subset of follicular, marginal zone, lymphoplasmacytic, lymphoblastic, classical Hodgkin, mature T-cell and natural killer cell lymphomas and acute myeloid leukemias also expressed cyclin-D2 and D3. These data support the hypothesis that dysregulation of cell-cycle control by D-cyclins contribute to the pathogenesis of hematolymphoid neoplasia, and suggest a potential role for these proteins in the prognostic and therapeutic aspects of these diseases. For diagnostic purposes, however, the expression of D-cyclin proteins should be interpreted with caution in the subclassification of lymphoma types.

Hypermethylation of CD44 Is Characteristic of Specific Lymphoma Subtypes.

Abstract 3469Poster Board III-357Epigenetic inactivation of tumor suppressor genes (TSG) by promoter CpG island hypermethylation is a common hallmark of cancer. It is generally agreed, that CpG island hypermethylation profiles are specific for different tumor types [Costello et al., 2000, Nat Genet 25:132-138]. Using MS-MLPA (methylation-specific multiplex ligation-dependent probe amplification), methylation of 24 different TSG was analyzed in 40 lymphoma cell lines representing Hodgkin lymphoma (HL), anaplastic large cell lymphoma (ALCL), Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and mantle cell lymphoma (MCL). On average 8 ± 2.8 TSG out of the 24 analyzed were methylated per lymphoma cell line, whereas 0/24 TSG were methylated in healthy donor tonsils. Methylation frequencies decreased from HL, ALCL, BL, FL, DLBCL to MCL cell lines. The TSG methylation status of the most relevant genes was verified by methylation-specific PCR. Moreover, TSG hypermethylation correlated with transcriptional silencing as assessed by quantitative real time PCR. While our studies on the methylation status of TSG in lymphoma cell lines support previous methylation analyses performed on primary lymphoma patient material for many of the genes analyzed here, MS-MLPA screening also revealed a new interesting candidate: CD44. Hypermethylation of CD44 was characteristic of ALCL, BL, FL and DLBCL cell lines and allowed their discrimination from MCL and HL cell lines. In CD44 hypermethylated cell lines expression of CD44 was re-inducible at mRNA and protein levels by treatment with the demethylating agent 5-Aza-2'-deoxycytidine, confirming its epigenetic regulation. Furthermore, CD44 ligation with an anti-CD44 antibody induced apoptosis in CD44+ (CD44 unmethylated) lymphoma cell lines whereas CD44 hypermethylated cell lines showed no response. Thus, CD44 might be an interesting new epigenetic marker and a potential molecular target for the diagnosis and treatment of specific lymphoma subtypes. DisclosuresNo relevant conflicts of interest to declare.

Distinctive cell properties of B cells carrying theBCL2translocation and their potential roles in the development of lymphoma of germinal center type

The BCL2/IGH translocation is a hallmark of follicular lymphoma and germinal center B-cell type diffuse large B-cell lymphoma. Although a strong determinant of these histological subtypes, this translocation is insufficient by itself for lymphomagenesis, so that other genetic alterations are required. To clarify how the BCL2 translocation contributes to the development of specific lymphoma subtypes, we used chimeric mouse models and a bone marrow transplantation system to examine the biological features of BCL2-overexpressing B cells. These cells showed a cell-autonomous differentiation preference for follicular B cells. Their cell cycle progression was enhanced in wild-type but not in Emu-BCL2 transgenic mice, indicating that the low proliferative activity of B cells in Emu-BCL2 transgenic mice is partly due to their specific microenvironment, which is caused by the abnormal B cells themselves. Moreover, in vitro experiments demonstrated that Emu-BCL2(+) B cells have reduced responsiveness to terminal differentiation stimulation. According to these results, we hypothesize that B cells that have undergone BCL2/IGH translocation might possibly be forced to localize in follicles, and accumulate genetic abnormalities by being subjected to recurrent stimulation. Our findings lead us to propose that B cells carrying the BCL2/IGH translocation comprise a distinctive cell population that leads to the development of germinal center B-cell type lymphoma.

Highly increased familial risks for specific lymphoma subtypes

Studies have shown that familial risk contributes to aetiology of lymphomas. Using large population registries from Sweden, we evaluated risk of lymphoma subtypes among first-degree relatives of 2668 follicular lymphoma (FL) patients, 2517 diffuse large B-cell lymphoma (DLBCL) patients, and 6963 Hodgkin lymphoma (HL) patients compared to first-degree relatives of controls. Relatives were at the highest risk for developing the same lymphoma subtype as the case. DLBCL was increased 10-fold among relatives of DLBCL patients, FL was increased fourfold among relatives of FL patients and HL was increased fourfold among relatives of HL patients. These results imply that germline susceptibility genes are specific to lymphoma subtype.