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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate the mechanisms underlying chromosomal translocations in diffuse large B cell lymphoma (DLBCL), we investigated the nature and extent of immunoglobulin class switch recombination (CSR) in these tumors. We used Southern blotting to detect legitimate and illegitimate CSR events in tumor samples of the activated B cell-like (ABC), germinal center B cell-like (GCB), and primary mediastinal B cell lymphoma (PMBL) subgroups of DLBCL. The frequency of legitimate CSR was lower in ABC DLBCL than in GCB DLBCL and PMBL. In contrast, ABC DLBCL had a higher frequency of internal deletions within the switch mu (Smu) region compared with GCB DLBCL and PMBL. ABC DLBCLs also had frequent deletions within Sgamma and other illegitimate switch recombinations. Sequence analysis revealed ongoing Smu deletions within ABC DLBCL tumor clones, which were accompanied by ongoing duplications and activation-induced cytidine deaminase-dependent somatic mutations. Unexpectedly, short fragments derived from multiple chromosomes were interspersed within Smu in one case. These findings suggest that ABC DLBCLs have abnormalities in the regulation of CSR that could predispose to chromosomal translocations. Accordingly, aberrant switch recombination was responsible for translocations in ABC DLBCLs involving BCL6, MYC, and a novel translocation partner, SPIB.
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PMID:Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma. 1735 67

In the World Health Organization classification, cases with classical Burkitt morphologic features and a very high proliferation fraction but without the MYC translocation are not clearly designated as a separate entity and are usually categorized as diffuse large B-cell lymphoma (DLBCL). We identified from our records 33 cases of highly aggressive mature B-cell neoplasms from 8 children and 25 adults with typical Burkitt cytomorphologic, histologic, and immunophenotypic (CD20+/CD10+ and surface immunoglobulin-positive) features. Rearrangement of MYC (MYC+) was present in only 18 of 33 cases, but the proliferation fraction was more than 90% in all MYC-cases (no MYC rearrangement). The immunophenotype of the lymphoma cells in the 2 groups was similar. Although children with MYC+ and MYC- neoplasms were treated with chemotherapy regimens appropriate for Burkitt lymphoma, adults with MYC- lymphomas received less aggressive therapy usually given for DLBCL. Survival analysis showed that adults in the MYC- group had an inferior outcome compared with adults with MYC+ disease. Provisional identification of MYC- lymphomas with typical Burkitt morphologic features as an entity separate from DLBCL will facilitate further studies and possible categorization as a separate entity.
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PMID:Clinicopathologic findings in high-grade B-cell lymphomas with typical Burkitt morphologic features but lacking the MYC translocation. 1802 24

Somatic hypermutation (SHM) aberrantly targets proto-oncogenes in various non-Hodgkin's lymphoma. To test the association of SHM with transformation of follicular lymphoma (FL), we sequenced mutational hot spots in five proto-oncogenes (BCL6, PAX5, RHOH, MYC and PIM1) in 32 low-grade FL (lgFL) with follicular histology and 26 transformed FL (tFL) with diffuse large cell histology. No difference was detected in the fraction of specimens mutated (75% of lgFL and 77% of tFL) or in the mutation load (0.08 for lgFL vs. 0.06 mutations/100 bp/allele for tFL). Serial specimens were examined from 25 patients showing stable low-grade FL (slgFL; n=6) or a low-grade FL that later transformed into diffuse large cell lymphoma (tFL; n=19). slgFL and tFL patients accumulated similar numbers of mutations in the interval between biopsies. These data indicate that mutations attributable to aberrant SHM occur with similar frequency in low-grade and transformed FL; transformation is not associated with a higher rate of aberrant SHM. Moreover, the frequency of mutations attributable to aberrant SHM in tFL was significantly lower than that reported for de novo diffuse large B cell lymphoma, suggesting differing oncogenic mechanisms in transformed follicular lymphoma and de novo diffuse large B cell lymphoma.
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PMID:Quantifying the role of aberrant somatic hypermutation in transformation of follicular lymphoma. 1818 34

B-cell lymphomas/leukemias with simultaneous t(14;18)(q32;q21) and MYC rearrangements have recently been shown to constitute a separate diagnostic entity, presenting with a rapid clinical course and a very poor prognosis. We describe the establishment of an Epstein-Barr virus negative cell line, designated U-2973, from a male patient with a de novo aggressive B-cell lymphoma/leukemia and very high peripheral blast cell count. Flow cytometry of bone marrow cells and U-2973 displayed a mature B-cell phenotype, and immunostaining showed expression of MYC and BCL2. IG gene rearrangement data were consistent with a lymphoid neoplasm of germinal centre derivation. Cytogenetic studies using conventional G-banding, fluorescent in situ hybridization, spectral karyotyping and single nucleotide polymorphism array demonstrated a complex karyotype with both a t(14;18) and double translocations between MYC and a non-IG gene partner located at chromosome 12p12.1.
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PMID:U-2973, a novel B-cell line established from a patient with a mature B-cell leukemia displaying concurrent t(14;18) and MYC translocation to a non-IG gene partner. 1851 Jul 4

Gene expression profiling (GEP) on frozen tissues has identified genes predicting outcome in patients with diffuse large B-cell lymphoma (DLBCL). Confirmation of results in current patients is limited by availability of frozen samples and addition of monoclonal antibodies to treatment regimens. We used a quantitative nuclease protection assay (qNPA) to analyze formalin-fixed, paraffin-embedded tissue blocks for 36 previously identified genes (N = 209, 93 chemotherapy; 116 rituximab + chemotherapy). By qNPA, 208 cases were successfully analyzed (99.5%). In addition, 15 of 36 and 11 of 36 genes, representing each functional group previously identified by GEP, were associated with survival (P < .05) in the 2 treatment groups, respectively. In addition, 30 of 36 hazard ratios of death trended in the same direction versus the original studies. Multivariate and variable cut-off point analysis identified low levels of HLA-DRB (< 20%) and high levels of MYC (> 80%) as independent indicators of survival, together distinguishing cases with the worst prognosis. Our results solve a clinical research problem by demonstrating that prognostic genes can be meaningfully quantified using qNPA technology on formalin-fixed, paraffin-embedded tissues; previous GEP findings in DLBCL are relevant with current treatments; and 2 genes, representing immune escape and proliferation, are the common features of the most aggressive DLBCL.
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PMID:Gene expression predicts overall survival in paraffin-embedded tissues of diffuse large B-cell lymphoma treated with R-CHOP. 1884 Jul 22

Recent retrospective studies of heterogeneously treated patients have suggested that chromosomal aberrations of the MYC gene locus indicate an unfavorable prognosis in diffuse large B-cell lymphoma (DLBCL). Here, we investigated the prognostic impact of MYC aberrations analyzed by interphase fluorescence in situ hybridization in 177 patients with de novo DLBCL treated within the two prospective, randomized trials non-Hodgkin's lymphoma NHL-B1 and NHL-B2. MYC aberrations were detected in 14 DLBCL (7.9%). In a univariate analysis compared with MYC-negative DLBCL, MYC-positive cases showed a significantly shorter overall survival (OS) (P=0.047) and relevantly, though not significantly, shorter event-free survival (EFS) (P=0.062). In a Cox model adjusted for the international prognostic index, the presence of a MYC gene rearrangement was the strongest statistically independent predictor of OS (relative risk 3.4, P=0.004) and EFS (relative risk 2.5, P=0.015), and this also held true when the cell-of-origin signature detected by immunohistochemistry was included in the model.
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PMID:Structural aberrations affecting the MYC locus indicate a poor prognosis independent of clinical risk factors in diffuse large B-cell lymphomas treated within randomized trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL). 1875 28

Clinical studies showed that advanced stage, high LDH, poor response to reduction therapy and combined bone marrow and central nervous system disease are significantly associated with a decreased event-free survival (EFS) in pediatric mature B-cell non-Hodgkin's lymphoma (B-NHL) treated on FAB/LMB96. Although rearranged MYC/8q24 (R8q24) is characteristic of Burkitt lymphoma (BL), little information is available on other cytogenetic abnormalities and their prognostic importance. We performed an international review of 238 abnormal karyotypes in childhood mature B-NHL treated on FAB/LMB96: 76% BL, 8% Burkitt-like lymphoma, 13% diffuse large B-cell lymphoma (DLBCL). The main BL R8q24-associated chromosomal aberrations were +1q (29%), +7q and del(13q) (14% each). The DLBCL appeared heterogeneous and more complex. Incidence of R8q24 (34%) was higher than reported in adult DLBCL. The prognostic value of cytogenetic abnormalities on EFS was studied by Cox model controlling for the known risk factors: R8q24, +7q and del(13q) were independently associated with a significant inferior EFS (hazard ratio: 6.1 (P=0.030), 2.5 (P=0.015) and 4.0 (P=0.0003), respectively). The adverse prognosis of R8q24 was observed only in DLBCL, whereas del(13q) and +7q had a similar effect in DLBCL and BL. These results emphasize the significant biological heterogeneity and the development of cytogenetic risk-adapted therapy in childhood mature B-NHL.
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PMID:Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. 1902 May 48

Signals that control the fine balance between cell death and cell survival are altered during tumorigenesis. Understanding the mechanisms by which this balance is perturbed, leading to excessive cell survival, is important for designing effective therapies. Proteins belonging to the B-cell lymphoma (BCL) family are known to regulate death responses to apoptotic signals, especially those originating within cells. A subset of BCL family members capable of inhibiting cell death is known to contribute to tumorigenesis; however, it is not known whether all six antiapoptotic BCL family members play a causal role in tumor development. Using a mouse model of MYC-driven leukemia, we showed that, in addition to the well characterized BCL2 and BCLxl (BCL2L1), the other four family members -- BCLw (BCL2L2), BCLb (BCL2L10), BFL1 (BCL2A1) and MCL1 -- also cooperate with MYC to accelerate leukemogenesis. In addition, high levels of each family member are found in either solid human tumors or cell lines derived from human leukemias or lymphomas.
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PMID:MYC-induced myeloid leukemogenesis is accelerated by all six members of the antiapoptotic BCL family. 1913 12

Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma. Although it is a curable disease, fewer than half of patients are cured with conventional chemotherapy. The highly variable outcome reflects a heterogeneous group of tumors, with different genetic abnormalities and responses to therapy. We analyzed 74 cases of diffuse large B-cell lymphoma using interphase fluorescent in situ hybridization with commercially available probes for split-signal targeting BCL-2, BCL-6, MYC, BCL-10, and MALT-1. Gene rearrangements were identified in 48 (65%) of 74 cases. BCL-6 was the most rearranged gene (45%), followed by BCL-2 (21%), BCL-10 (18%), and MYC (16%). No MALT-1 rearrangements were found. When diffuse large B-cell lymphoma cases were subdivided into germinal-center B-cell-like and activated B-cell-like groups, an inverse pattern of BCL-2 and BCL-6 rearrangements was observed. Of interest, the presence of chromosome rearrangements was associated with a worse prognosis. The pattern of cytogenetic abnormalities highlighted the fact not only that diffuse large B-cell lymphoma is a heterogeneous entity but also that even individual cases may contain subclones bearing different chromosomal rearrangements. The relevance and the clinical implication of minor clones showing gene rearrangements are poorly understood; however, this first observation suggests that different rearrangements may be involved in the progression of the disease. The fluorescent in situ hybridization analysis with the panel used in this study is useful to detect the heterogeneity of diffuse large B-cell lymphomas and identify alterations with prognostic implications.
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PMID:BCL2, BCL6, MYC, MALT 1, and BCL10 rearrangements in nodal diffuse large B-cell lymphomas: a multicenter evaluation of a new set of fluorescent in situ hybridization probes and correlation with clinical outcome. 1952 6

The MYC family of cellular oncogenes includes c-Myc, N-myc, and L-myc, which encode transcriptional regulators involved in the control of cell proliferation and death. Accordingly, these genes become aberrantly activated and expressed in specific types of cancers. For example, c-Myc translocations occur frequently in human B lymphoid tumors, while N-myc gene amplification is frequent in human neuroblastomas. The observed association between aberrations in particular MYC family genes and specific subsets of malignancies might reflect, at least in part, tissue-specific differences in expression or function of a given MYC gene. Since c-Myc and N-myc share substantial functional redundancy, another factor that could influence tumor-specific gene activation would be mechanisms that target aberrations (e.g., translocations) in a given MYC gene in a particular tumor progenitor cell type. We have previously shown that mice deficient for the DNA Ligase4 (Lig4) nonhomologous DNA end-joining factor and the p53 tumor suppressor routinely develop progenitor (pro)-B cell lymphomas that harbor translocations leading to c-Myc amplification. Here, we report that a modified allele in which the c-Myc coding sequence is replaced by N-myc coding sequence (NCR allele) competes well with the wild-type c-Myc allele as a target for oncogenic translocations and amplifications in the Lig4/p53-deficient pro-B cell lymphoma model. Tumor onset, type, and cytological aberrations are similar in tumors harboring either the wild-type c-Myc gene or the NCR allele. Our results support the notion that particular features of the c-Myc locus select it as a preferential translocation/amplification target, compared to the endogenous N-myc locus, in Lig4/p53-deficient pro-B cell lymphomas.
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PMID:Chromosomal location targets different MYC family gene members for oncogenic translocations. 1917 20


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