Expression of microRNAs in diffuse large B cell lymphoma is associated with immunophenotype, survival and transformation from follicular lymphoma

MicroRNAs are naturally occurring small RNA species that regulate gene expression and are frequently abnormally expressed in cancers. However, the role of microRNAs in lymphoma is poorly understood. Therefore, we undertook a comprehensive study of microRNA expression in two of the most common lymphomas: diffuse large B-cell lymphoma (DLBCL) ( n = 80) and follicular lymphoma (FCL) ( n = 18) using microarrays containing probes for 464 human microRNAs. Unsupervised cluster analysis revealed distinct expression patterns between these two lymphomas and specific microRNA signatures (including members of the miR-17–92 cluster) were derived that correctly predicted lymphoma type in >95% of cases. Furthermore, we identified microRNAs in de novo DLBCL ( n = 64) associated with germinal centre-like and non-germinal centre-like immunophenotypes, international prognostic index status and event-free survival in CHOP and rituximab (R)-CHOP treated patients. Despite the indolent nature of FCL a significant proportion of cases undergo high-grade transformation to more aggressive DLBCL. In order to see if transformation is associated with changes in microRNA expression we compared transformed DLBCL cases ( n = 16) with de novo DLBCL, as well as FCL cases that underwent subsequent transformation ( n = 7) with FCL cases that had not transformed at a median follow-up of 60 months ( n = 11). Differential expression of 12 microRNAs correctly predicted >85% of transformed versus de novo DLBCL cases; six microRNAs ( miR-223, 217, 222 , 221 and let-7i and 7b) were found which could similarly predict or transformation in FCL ( P < 0.05). These data suggest that microRNAs have potential as diagnostic and prognostic markers in these lymphomas and may be used to identify FCL patients at risk of high-grade transformation.     

FOXP1 molecular cytogenetics and protein expression analyses in primary cutaneous large B cell lymphoma, leg-type

FOXP1 protein is expressed in normal activated B cells and overexpressed in a subset of diffuse large B-cell lymphomas, including primary cutaneous large B-cell lymphomas (PCLBCL), leg type. High expression of FOXP1 has been associated to an unfavourable prognosis with independent survival significance. However, little is known regarding the mechanisms underlying the overexpression of FOXP1 in PCLBCL, leg type. Our aims were to analyze FOXP1 cytogenetic status and protein expression in a series of PCLBCL, leg type. Finally, we compared the observed results with those obtained in a group of patients with primary cutaneous follicle centre lymphoma (PCFCL). Fifteen patients with PCLBCL, leg type and nine patients with primary cutaneous follicle centre lymphoma (PCFCL) were included in the study. For each biopsy specimen, FOXP1 translocation and copy number changes were evaluated by fluorescence in situ hybridization (FISH) and protein expression by immunohistochemistry (IHC). Immunohistochemistry showed FOXP1 staining in 13 PCLBCL, leg type, whereas all PCFCL were negative. FISH analysis disclosed no translocations involving FOXP1 gene in any of the cases. However, FOXP1 gene gains (3 to 4 copies) were observed in 82% of samples of PCLBCL, leg type and in 37% of PCFCL. FOXP1 expression was independent from FOXP1 translocation. Our results confirm that overexpression of FOXP1 is present in a considerable proportion of PCLBCL, leg type and might indicate an unfavourable prognosis. Mechanisms not related to translocation seem to be responsible for this overexpression.     

中枢神经系统弥漫大B 细胞淋巴瘤相关microRNAs 的研究进展

中枢神经系统(central nervous system,CNS)复发是弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)的一种不常见的严重的并发症,新诊断的患者2年内易于发生,最常见于非霍奇金淋巴瘤弥漫大B细胞型(non-Hodgkin diffuse large B-cell lymphoma-,NHL-DLBCL),目前,对于初始治疗后出现中枢复发其发病机制并不清楚。microRNA(miRNA)是一类新发现的非编码小分子RNA,通过抑制靶基因翻译或降解靶miRNA调控基因表达,参与细胞分化、增殖、调亡等生命活动。miRNA在淋巴瘤的发生发展中有重要作用。近年来大量研究已证实miRNA与肿瘤的组织来源、进展、转移预后与耐药都密切相关,既可作为抑癌基因,也可作为癌基因。淋巴瘤是一种血液免疫系统肿瘤,与淋巴瘤相关的miRNA已成为当前研究热点之一。microRNAs的功能紊乱如何导致DLBCL发生的机制目前还没有得到很好的证明,但DLBCL患者中464种miRNAs显示microRNA(包括miRNA-17-92簇)预测淋巴瘤的准确率达95%,为淋巴瘤研究提供了新依据。     

Epstein-Barr virus-induced gene 3 (EBI3): a novel diagnosis marker in Burkitt lymphoma and diffuse large B-cell lymphoma

The distinction between Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), two types of mature aggressive B-cell lymphomas that require distinct treatments, can be difficult because of forms showing features intermediate between DLBCL and BL (here called BL/DLBCL). They can be discriminated by the presence of c-myc translocations characteristic of BL. However, these are not exclusive of BL and when present in DLBCL are associated with lower survival. In this study, we show that Epstein-Barr virus-induced gene 3 (EBI3) is differentially expressed among BL and DLBCL. Analysis of gene expression data from 502 cases of aggressive mature B-cell lymphomas available on Gene Expression Omnibus and immunohistochemical analysis of 184 cases of BL, BL/DLBCL or DLBCL, showed that EBI3 was not expressed in EBV-positive or -negative BL cases, whereas it was expressed by over 30% of tumoral cells in nearly 80% of DLBCL cases, independently of their subtypes. In addition, we show that c-myc overexpression represses EBI3 expression, and that DLBCL or BL/DLBCL cases with c-myc translocations have lower expression of EBI3. Thus, EBI3 immunohistochemistry could be useful to discriminate BL from DLBCL, and to identify cases of BL/DLBCL or DLBCL with potential c-myc translocations.     

Comprehensive miRNA sequence analysis reveals survival differences in diffuse large B-cell lymphoma patients

BackgroundDiffuse large B-cell lymphoma (DLBCL) is an aggressive disease, with 30% to 40% of patients failing to be cured with available primary therapy. microRNAs (miRNAs) are RNA molecules that attenuate expression of their mRNA targets. To characterize the DLBCL miRNome, we sequenced miRNAs from 92 DLBCL and 15 benign centroblast fresh frozen samples and from 140 DLBCL formalin-fixed, paraffin-embedded tissue samples for validation.ResultsWe identify known and candidate novel miRNAs, 25 of which are associated with survival independently of cell-of-origin and International Prognostic Index scores, which are established indicators of outcome. Of these 25 miRNAs, six miRNAs are significantly associated with survival in our validation cohort. Abundant expression of miR-28-5p, miR-214-5p, miR-339-3p, and miR-5586-5p is associated with superior outcome, while abundant expression of miR-324-5p and NOVELM00203M is associated with inferior outcome. Comparison of DLBCL miRNA-seq expression profiles with those from other cancer types identifies miRNAs that were more abundant in B-cell contexts. Unsupervised clustering of miRNAs identifies two clusters of patients that have distinct differences in their outcomes. Our integrative miRNA and mRNA expression analyses reveal that miRNAs increased in abundance in DLBCL appear to regulate the expression of genes involved in metabolism, cell cycle, and protein modification. Additionally, these miRNAs, including one candidate novel miRNA, miR-10393-3p, appear to target chromatin modification genes that are frequent targets of somatic mutation in non-Hodgkin lymphomas.ConclusionsOur comprehensive sequence analysis of the DLBCL miRNome identifies candidate novel miRNAs and miRNAs associated with survival, reinforces results from previous mutational analyses, and reveals regulatory networks of significance for lymphomagenesis.

Electronic supplementary material

The online version of this article (doi:10.1186/s13059-014-0568-y) contains supplementary material, which is available to authorized users.     

Differential microRNA Profiles and Their Functional Implications in Different Immunogenetic Subsets of Chronic Lymphocytic Leukemia

Critical processes of B-cell physiology, including immune signaling through the B-cell receptor (BcR) and/or Toll-like receptors (TLRs), are targeted by microRNAs. With this in mind and also given the important role of BcR and TLR signaling and microRNAs in chronic lymphocytic leukemia (CLL), we investigated whether microRNAs could be implicated in shaping the behavior of CLL clones with distinct BcR and TLR molecular and functional profiles. To this end, we examined 79 CLL cases for the expression of 33 microRNAs, selected on the following criteria: (a) deregulated in CLL versus normal B-cells; (b) differentially expressed in CLL subgroups with distinct clinicobiological features; and, (c) if meeting (a) + (b), having predicted targets in the immune signaling pathways. Significant upregulation of miR-150, miR-29c, miR-143 and miR-223 and downregulation of miR-15a was found in mutated versus unmutated CLL, with miR-15a showing the highest fold difference. Comparison of two major subsets with distinct stereotyped BcRs and signaling signatures, namely subset 1 [IGHV1/5/7-IGKV1(D)-39, unmutated, bad prognosis] versus subset 4 [IGHV4-34/IGKV2-30, mutated, good prognosis] revealed differences in the expression of miR-150, miR-29b, miR-29c and miR-101, all down-regulated in subset 1. We were also able to link these distinct microRNA profiles with cellular phenotypes, importantly showing that, in subset 1, miR-101 downregulation is associated with overexpression of the enhancer of zeste homolog 2 (EZH2) protein, which has been associated with clinical aggressiveness in other B-cell lymphomas. In conclusion, specific miRNAs differentially expressed among CLL subgroups with distinct BcR and/or TLR signaling may modulate the biological and clinical behavior of the CLL clones.     

Overexpression of microRNAs from the miR-17-92 paralog clusters in AIDS-related non-Hodgkin's lymphomas

Background

Individuals infected by HIV are at an increased risk for developing non-Hodgkin''s lymphomas (AIDS-NHL). In the highly active antiretroviral therapy (HAART) era, there has been a significant decline in the incidence of AIDS-associated primary central nervous system lymphoma (PCNSL). However, only a modest decrease in incidence has been reported for other AIDS-NHL subtypes. Thus, AIDS-NHLs remain a significant cause of morbidity and mortality in HIV infected individuals. Recently, much attention has been directed toward the role of miRNAs in cancer, including NHL. Several miRNAs, including those encoded by the miR-17-92 polycistron, have been shown to play significant roles in B cell tumorigenesis. However, the role of miRNAs in NHL in the setting of HIV infection has not been defined.

Methodology/Principal Findings

We used quantitative realtime PCR to assess the expression of miRNAs from three different paralog clusters, miR-17-92, miR-106a-363, and miR-106b-25 in 24 cases of AIDS-NHLs representing four tumor types, Burkitt''s lymphoma (BL, n = 6), diffuse large B-cell lymphoma (DLBCL, n = 8), primary central nervous system lymphoma (PCNSL, n = 5), and primary effusion lymphoma (PEL, n = 5). We also used microarray analysis to identify a differentiation specific miRNA signature of naïve, germinal center, and memory B cell subsets from tonsils (n = 4). miRNAs from the miR-17-92 paralog clusters were upregulated by B cells, specifically during the GC differentiation stage. We also found overexpression of these miRNA clusters in all four AIDS-NHL subtypes. Finally, we also show that select miRNAs from these clusters (miR-17, miR-106a, and miR-106b) inhibited p21 in AIDS-BL and DLBCL cases, thus providing a mechanistic role for these miRNAs in AIDS-NHL pathogenesis.

Conclusion

Dysregulation of miR-17-92 paralog clusters is a common feature of AIDS-associated NHLs.     

MicroRNA and target protein patterns reveal physiopathological features of glioma subtypes

Gliomas such as oligodendrogliomas (ODG) and glioblastomas (GBM) are brain tumours with different clinical outcomes. Histology-based classification of these tumour types is often difficult. Therefore the first aim of this study was to gain microRNA data that can be used as reliable signatures of oligodendrogliomas and glioblastomas. We investigated the levels of 282 microRNAs using membrane-array hybridisation and real-time PCR in ODG, GBM and control brain tissues. In comparison to these control tissues, 26 deregulated microRNAs were identified in tumours and the tissue levels of seven microRNAs (miR-21, miR-128, miR-132, miR-134, miR-155, miR-210 and miR-409-5p) appropriately discriminated oligodendrogliomas from glioblastomas. Genomic, epigenomic and host gene expression studies were conducted to investigate the mechanisms involved in these deregulations. Another aim of this study was to better understand glioma physiopathology looking for targets of deregulated microRNAs. We discovered that some targets of these microRNAs such as STAT3, PTBP1 or SIRT1 are differentially expressed in gliomas consistent with deregulation of microRNA expression. Moreover, MDH1, the target of several deregulated microRNAs, is repressed in glioblastomas, making an intramitochondrial-NAD reduction mediated by the mitochondrial aspartate-malate shuttle unlikely. Understanding the connections between microRNAs and bioenergetic pathways in gliomas may lead to identification of novel therapeutic targets.     

Genomic profiling using array comparative genomic hybridization define distinct subtypes of diffuse large b-cell lymphoma: a review of the literature

ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin Lymphoma comprising of greater than 30 % of adult non-Hodgkin Lymphomas. DLBCL represents a diverse set of lymphomas, defined as diffuse proliferation of large B lymphoid cells. Numerous cytogenetic studies including karyotypes and fluorescent in situ hybridization (FISH), as well as morphological, biological, clinical, microarray and sequencing technologies have attempted to categorize DLBCL into morphological variants, molecular and immunophenotypic subgroups, as well as distinct disease entities. Despite such efforts, most lymphoma remains undistinguishable and falls into DLBCL, not otherwise specified (DLBCL-NOS). The advent of microarray-based studies (chromosome, RNA, gene expression, etc) has provided a plethora of high-resolution data that could potentially facilitate the finer classification of DLBCL. This review covers the microarray data currently published for DLBCL. We will focus on these types of data; 1) array based CGH; 2) classical CGH; and 3) gene expression profiling studies. The aims of this review were three-fold: (1) to catalog chromosome loci that are present in at least 20 % or more of distinct DLBCL subtypes; a detailed list of gains and losses for different subtypes was generated in a table form to illustrate specific chromosome loci affected in selected subtypes; (2) to determine common and distinct copy number alterations among the different subtypes and based on this information, characteristic and similar chromosome loci for the different subtypes were depicted in two separate chromosome ideograms; and, (3) to list re-classified subtypes and those that remained indistinguishable after review of the microarray data. To the best of our knowledge, this is the first effort to compile and review available literatures on microarray analysis data and their practical utility in classifying DLBCL subtypes. Although conventional cytogenetic methods such as Karyotypes and FISH have played a major role in classification schemes of lymphomas, better classification models are clearly needed to further understanding the biology, disease outcome and therapeutic management of DLBCL. In summary, microarray data reviewed here can provide better subtype specific classifications models for DLBCL.     

Genotypic and Phenotypic Differences between Nodal and Extranodal Diffuse Large B-Cell Lymphomas

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of diseases that have diverse clinical, pathological, and biological features. Here, it is shown that primary nodal and extranodal DLBCLs differ genomically and phenotypically. Using conventional comparative genomic hybridization (CGH), the authors assessed the chromosomal aberrations in 18 nodal, 13 extranodal, and 5 mixed DLBCLs. The results demonstrate significantly distinct chromosomal aberrations exemplified by gains of chromosomal arms 1p, 7p, 12q24.21-12q24.31, and 22q and chromosome X and loss of chromosome 4, 6q, and 18q22.3-23 in extranodal compared with nodal DLBCLs. Nodal DLBCLs showed an increased tendency for 18q amplification and BCL2 protein overexpression compared with extranodal and mixed tumors. Using a panel of five antibodies against GCET1, MUM1, CD10, BCL6, and FOXP1 proteins to subclassify DLBCLs according to the recent Choi algorithm, the authors showed that the genomic profiles observed between the nodal and extranodal DLBCLs were not due to the different proportions of GCB vs ABC in the two groups. Further delineation of these genomic differences was illuminated by the use of high-resolution 21K BAC array CGH performed on 12 independent new cases of extranodal DLBCL. The authors demonstrated for the first time a novel genome and proteome-based signatures that may differentiate the two lymphoma types.     

乳腺恶性血液病的病理类型、临床特点及生存分析

目的:探讨乳腺恶性血液病的病理分型、患者的临床特征及预后。方法:回顾性分析2014年1月至2019年1月空军军医大学西京医院收治的33例乳腺恶性血液病患者的病理分型、临床特征及预后。结果:33例患者中,32例为女性,1例为男性,平均年龄为45.5岁(12-78岁)。经病理确诊29例(29/33,87.9%)为非霍奇金淋巴瘤,其中弥漫大B细胞淋巴瘤(18/29,62.1%)最为常见,其次是NK/T细胞淋巴瘤(3/29,10.3%),B淋巴母细胞白血病/淋巴瘤(2/29,6.8%),而伯基特淋巴瘤、滤泡淋巴瘤、原发皮肤间变大细胞淋巴瘤各1例(1/29,3.4%),其余3例未进一步分型。此外,1例(1/33,3.0%)霍奇金淋巴瘤,3例(3/33,9.1%)急性白血病复发累及乳腺。原发性乳腺恶性血液病为19例(57.6%),继发性为14例(42.4%),病变主要累及右侧乳腺(18例,54.5%),其次为左侧(10例,30.3%),双侧均累及的为少数(5例,15.2%)。19例原发性乳腺恶性血液病均为淋巴瘤,与14例继发性乳腺恶性血液病相比,其血小板计数明显升高(P=0.004),β2-MG显著降低(P=0.049),B症状少(P=0.017),Ann Arbor分期主要为Ⅰ-Ⅱ期(P<0.01),骨髓受累少(P<0.01)等特点。生存分析提示原发性乳腺恶性血液病患者比继发性患者生存期更长(HR=9.846,P=0.002)。恶性血液病累及骨髓可导致生存期显著缩短(HR=6.434,P<0.01)。结论:乳腺恶性血液病患者以中年女性为主,原发性乳腺恶性血液病比继发性发病率高(分别为57.5%和42.5%),最常见的病理类型为弥漫大B细胞淋巴瘤,病变主要累及右侧乳腺。与继发性乳腺恶性血液病相比,原发性乳腺恶性血液病患者具有血小板计数相对更高,β2-MG水平更低,往往不伴B症状,Ann Arbor分期主要为Ⅰ-Ⅱ期,骨髓不受累,且生存期显著延长等特点。此外,恶性血液病累及骨髓提示预后不良。     

Effect of Xpcl1 activation and p27(Kip1) loss on gene expression in murine lymphoma

Mice lacking the p27(Kip1) Cdk inhibitor (Cdkn1b) exhibit increased susceptibility to lymphomas from the Maloney murine leukemia virus (M-MuLV), and exhibit a high frequency of viral integrations at Xpcl1 (Kis2), a locus on the X-chromosome. Xpcl1 encodes miR-106a~363, a cluster of microRNAs that are expressed in response to adjacent retroviral integrations. We report the first large-scale profile of microRNA expression in MuLV-induced lymphomas, in combination with microarray gene expression analysis. The source material was T-cell lymphomas induced by M-MuLV in p27(Kip1) knockout mice and normal thymus. Surprisingly, the overall levels of miRNA expression were equivalent in lymphomas and normal thymus. Nonetheless, the expression of specific microRNAs was altered in tumors. The miR-106a~363 miRNA were over-expressed in lymphomas, particularly those with viral integrations at the Xpcl1 locus. In contrast, p27(Kip1) deletion itself was associated with a different pattern of microRNA expression. Gene expression was dramatically altered in lymphomas, yet paralleled data from T-cell lymphomas induced by other mechanisms. Genes with altered expression in association with the p27(Kip1) null genotype were of similar functional classes to those associated with Xpcl1 integration, but with the opposite pattern of expression. Thus, the effect of p27(Kip1) deletion may be to oppose an anti-oncogenic effect of Xpcl1 rather than enhancing its oncogenic functions. A subset of miR-106a~363 target genes was consistently reduced in lymphomas with Xpcl1 integrations, particularly genes with cell cycle and immune functions. We identify four predicted target genes of miR-106a~363 miRNA, including N-Myc (Mycn), and the TGF-beta receptor (Tgfbr2) using 3'UTR reporter assays. Still, bioinformatic miRNA target predictions were poor predictors of altered gene expression in lymphomas with Xpcl1 integration. Confirmation of miR-106a~363 gene targeting relevant to the tumor phenotype requires in vivo validation, because only a subset of predicted targets are consistently reduced in tumors that overexpress miR-106a~363.     

Circulating miR-215-5p and miR-642a-5p as potential biomarker for diagnosis of osteosarcoma in Mexican population

Osteosarcoma is the most common malignant bone neoplasia affecting individuals in the second decade of life. The survival rate has not been improved during the last 25 years, in part because of the lack of specific markers. The microRNAs have been identified as important regulators of gene expression, experimental evidence suggests these molecules as key players in cancer development and progression. To identify miRNAs differentially expressed in serum from patients with osteosarcoma compared to healthy donors in Mexican population. Fifteen osteosarcoma patients and fifteen age and sex matched healthy individuals were recruited. Two pools of total RNA extracted from serum per study group were prepared and the miRNA expression profiles were analyzed through TaqMan Low Density Arrays. Validation was carried out through RT-qPCR using individual TaqMan assays for those miRNAs differentially expressed. Fifteen miRNAs were differentially expressed in osteosarcoma patients compared to healthy controls. Overexpression of miR-215-5p and miR-642a-5p was confirmed by validation through RT-qPCR. The expression analysis of miRNAs from serum in osteosarcoma patients revealed differential expression of miR-215-5p and miR-642a-5p. Both microRNAs are potential markers for osteosarcoma diagnosis.     

MicroRNA signatures differentiate melanoma subtypes

Melanoma is an aggressive cancer that is highly resistance to therapies once metastasized. We studied microRNA (miRNA) expression in clinical melanoma subtypes and evaluated different miRNA signatures in the background of gain of function somatic and inherited mutations associated with melanoma. Total RNA from 42 patient derived primary melanoma cell lines and three independent normal primary melanocyte cell cultures was evaluated by miRNA array. MiRNA expression was then analyzed comparing subtypes and additional clinicopathologic criteria including somatic mutations. The prevalence and association of an inherited variant in a miRNA binding site in the 3′UTR of the KRAS oncogene, referred to as the KRAS-variant, was also evaluated. We show that seven miRNAs, miR-142-3p, miR-486, miR-214, miR-218, miR-362, miR-650 and miR-31, were significantly correlated with acral as compared to non-acral melanomas (p < 0.04). In addition, we discovered that the KRAS-variant was enriched in non-acral melanoma (25%), and that miR-137 under expression was significantly associated with melanomas with the KRAS-variant. Our findings indicate that miRNAs are differentially expressed in melanoma subtypes and that their misregulation can be impacted by inherited gene variants, supporting the hypothesis that miRNA misregulation reflects biological differences in melanoma.Key words: melanoma, microRNA profiling, biomarker, acral, KRAS-variant, SNP     

P38 mitogen activated protein kinase expression and regulation by interleukin-4 in human B cell non-Hodgkin lymphomas

The prevalence and regulation of p38 mitogen activated protein kinase (MAPK) expression in human lymphomas have not been extensively studied. In order to elucidate the role of p38 MAPK in lymphomagenesis, we examined the expression of native and phosphorylated p38 (p-p38) MAPK in cell lines derived from human hematopoietic neoplasms including B cell lymphoma-derived cell lines using Western blot analysis. The p-p38 MAPK protein was also analyzed in 30 B cell non-Hodgkin lymphoma (NHL) tissue biopsies by immunohistochemistry. Our results show that the expression of p38 MAPK was up-regulated in most of the cell lines as compared with peripheral blood lymphocytes, while the expression of p-p38 MAPK was more variable. A subset of B cell NHL biopsies showed increased expression of p-p38 MAPK relative to reactive germinal center cells. Interleukin-4 (IL-4) induced a dose-dependent increase in the expression of p-p38 MAPK (1.6- to 2.8-fold) in cell lines derived from activated B cell-like diffuse large B cell lymphoma (DLBCL) but not those from germinal center-like DLBCL. No change was seen in native p38 MAPK. The in vitro kinase activity of p38 MAPK, however, was induced (1.6- to 3.2-fold) in all five cell lines by IL-4. Quantitative fluorescent RT-PCR demonstrated that all four isoforms of p38 MAPK gene were expressed in the lymphoma cell lines, with p38γ and p38β isoforms being predominant. IL-4 stimulation increased the expression of β, γ, and δ isoforms but not α isoform in two cell lines. In conclusion, there is constitutive expression and activation of p38 MAPK in a large number of B-lymphoma-derived cell lines and primary lymphoma tissues, supportive of its role in lymphomagenesis. The differential IL-4 regulation of p38 MAPK expression in cell lines derived from DLBCL may relate to the cellular origin of these neoplasms.

Electronic supplementary material

The online version of this article (doi:10.1007/s12308-009-0049-5) contains supplementary material, which is available to authorized users.