Significant Differences in the IGVH and BCL6 Mutation Status in Aggressive B-Cell Lymphomas with and without MYC Breakpoints.

Abstract Somatically mutated IGVH regions are a hallmark of germinal center (GC) B-cells. Moreover, aberrant somatic hypermutation (SHM) of oncogenes, like changes in the 5′ non-coding region of the BCL6 gene occurring in 75% of DLBCL, are a mechanism of oncogene activation independently of chromosomal translocations. Large scale mutational screening using DHPLC and direct sequencing was applied to determine the somatic hypermutation status of clonal IGVH as well as several oncogenes like BCL6 and MYC in a series of more than 250 aggressive B-cell lymphomas included in the Deutsche Krebshilfe funded network “Molecular Mechanisms in Malignant Lymphoma”. Mutation patterns were correlated with the results of molecular cytogenetic analyses. MYC breakpoints detected by FISH clearly differentiated two groups of aggressive B-NHL with significantly different VH mutation status. MYC-positive lymphomas by FISH carried VH genes with a mutation frequency significantly lower compared to aggressive lymphomas lacking these features (median 4.8% vs.11.,0%, p<0.0001). Similarly, the mutation frequency of BCL6 was significantly lower in MYC-positive than in MYC-negative lymphomas (median 0.13% vs 0.25% p=0,020). We observed a bias in VH gene usage in both groups with an overrepresentation of VH4 (40% in both groups) and VH3 gene (24% in MYC-positive, 40% in MYC-negative). The group of MYC-positive lymphomas was heterogeneous with regard to the pattern of chromosomal aberrations. (IGH, MYC, BCL2, BCL6, MALT1 and REL loci). Lymphomas with IG-MYC fusion lacking breakpoints in BCL2, BCL6, MALT1 or REL loci as well as non-MYC associated IGH translocations displayed a median IGVH mutation frequency of 4,8% vs. 12,2% in those cases with additional chromosomal translocations (p=0.0060). Molecular classification of aggressive B-cell lymphomas according to MYC breakpoints distinguishes subgroups with significant differences in the VH and BCL6 mutation frequencies.

Download Full-text

miR-181b negatively regulates activation-induced cytidine deaminase in B cells

Journal of Experimental Medicine ◽

10.1084/jem.20080579 ◽

2008 ◽

Vol 205 (10) ◽

pp. 2199-2206 ◽

Cited By ~ 162

Author(s):

Virginia G. de Yébenes ◽

Laura Belver ◽

David G. Pisano ◽

Susana González ◽

Aranzazu Villasante ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Molecular Mechanisms ◽

Bystander Effect ◽

Somatic Hypermutation ◽

Cytidine Deaminase ◽

Fine Tuning ◽

Functional Screening ◽

Activation Induced Cytidine Deaminase ◽

Activated B Cells

Activated B cells reshape their primary antibody repertoire after antigen encounter by two molecular mechanisms: somatic hypermutation (SHM) and class switch recombination (CSR). SHM and CSR are initiated by activation-induced cytidine deaminase (AID) through the deamination of cytosine residues on the immunoglobulin loci, which leads to the generation of DNA mutations or double-strand break intermediates. As a bystander effect, endogenous AID levels can also promote the generation of chromosome translocations, suggesting that the fine tuning of AID expression may be critical to restrict B cell lymphomagenesis. To determine whether microRNAs (miRNAs) play a role in the regulation of AID expression, we performed a functional screening of an miRNA library and identified miRNAs that regulate CSR. One such miRNA, miR-181b, impairs CSR when expressed in activated B cells, and results in the down-regulation of AID mRNA and protein levels. We found that the AID 3′ untranslated region contains multiple putative binding sequences for miR-181b and that these sequences can be directly targeted by miR-181b. Overall, our results provide evidence for a new regulatory mechanism that restricts AID activity and can therefore be relevant to prevent B cell malignant transformation.

Download Full-text

Aberrant Somatic Hypermutation in Primary Mediastinal Large B-Cell Lymphoma.

Blood ◽

10.1182/blood.v104.11.2268.2268 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2268-2268 ◽

Cited By ~ 1

Author(s):

Davide Rossi ◽

Michaela Cerri ◽

Daniela Capello ◽

Clara Deambrogi ◽

Eva Berra ◽

...

Keyword(s):

B Cell ◽

Base Pair ◽

Mutation Frequency ◽

Cell Lymphoma ◽

Somatic Hypermutation ◽

B Cell Lymphoma ◽

Single Base ◽

Large B Cell Lymphoma ◽

Single Base Pair ◽

Large B Cell

Abstract Primary mediastinal large B-cell lymphoma (PMLBCL) is recognised as a subtype of diffuse large B-cell lymphoma (DLBCL) arising in the mediastinum. With respect to DLBCL, PMLBCL displays specific clinical, molecular and morphological features suggesting that PMLBCL may represent a distinct clinico-pathologic entity. Aberrant somatic hypermutation (SHM) of PIM-1, PAX-5, RhoH/TTF and c-MYC has been advocated as a molecular feature distinctive of DLBCL. To investigate wether the same mechanism is associated with PMLBCL, we performed mutational analysis of PIM-1, PAX-5, RhoH/TTF and c-MYC in a panel of 19 PMLBCL. For comparison, 19 DLBCL were also analysed. For each gene, a region previously shown to contain >90% of mutations was analysed by PCR amplification and DNA direct sequencing. Overall, the prevalence of mutated cases was similar among DLBCL and PMLBCL. Mutations targeting at least one of the 4 genes were found in 14/19 (73.6%) PMLBCL and 13/19 (68.4%) DLBCL, while mutations in more than one gene were found in 7/19 (36.8%) PMLBCL and 9/19 (47.3%) DLBCL. Among the four genes, the prevalence of mutation and the mutation frequency was superimposable between PMLBCL and DLBCL. In fact, PAX-5 was mutated in 9/19 (47.3%) PMLBCL with a mean mutation frequency of 0.20 x 10−2/bp and in 7/19 (36.8%) DLBCL with a mean mutation frequency of 0.18 x 10−2/bp; RhoH/TTF was mutated in 6/19 (31.5%) PMLBCL with a mean mutation frequency of 0.08 x 10−2/bp and in 8/19 (42.1%) DLBCL with a mean mutation frequency of 0.27 x 10−2/bp; PIM-1 was mutated in 3/19 (15.7%) PMLBCL with a mean mutation frequency of 0.09 x 10−2/bp and in 7/19 (36.8%) DLBCL with a mean mutation frequency of 0.11 x 10−2/bp; c-MYC was mutated in 6/19 (31.5%) PMLBCL with a mean mutation frequency of 0.23 x 10−2/bp and in 5/19 (26.3%) DLBCL with a mean mutation frequency of 0.11 x 10−2. The mutation pattern was also similar between PMLBCL and DLBCL and was consistent with the SHM process. A total of 74 mutational events were detected in PMLBCL. The majority of mutations were represented by single base-pair substitution (n=66), whereas only 8 deletions of a short DNA stretch were observed. Of the 66 single base-pair substitutions, 41 were transitions and 25 were transversions, with a transition/transversion ratio of 1.64 and a G+C/A+T ratio of 3.6. Eleven out of 66 (16.6%) single base-pair substitutions felt within RGYW/WRCY motifs. Among DLBCL a total of 87 mutational events were detected. Mutations were preferentially represented by single base-pair substitutions (n=81), whereas only 4 deletions and 2 insertions of a short DNA stretch were observed. Of the 81 single base-pair substitutions, 42 were transitions and 39 were transversions, with a transition/transversion ratio of 1.07 and a G+C/A+T ratio of 1.89. Twenty six out of 81 (32.1%) single base-pair substitutions felt within RGYW/WRCY motifs. The implication of our results are twofold. First, aberrant SHM is involved in the pathogenesis of PMLBCL. Second, our results indicate that aberrant SHM targets both PMLBCL and DLBCL with similar prevalence, distribution and mutation pattern. Since aberrant SHM has been advocated as a molecular marker of DLBCL, our results corroborate the notion that PMLBCL represent a subtype of DLBCL rather than a distinct clinico-pathologic entity.

Download Full-text

Aberrant Somatic Hypermutation Targets an Extensive Set of Genes in Diffuse Large B-Cell Lymphoma.

Blood ◽

10.1182/blood.v104.11.1528.1528 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1528-1528 ◽

Cited By ~ 1

Author(s):

Laura Pasqualucci ◽

Roberta Guglielmino ◽

Sami N. Malek ◽

Urban Novak ◽

Mara Compagno ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Lines ◽

Cell Lymphoma ◽

Somatic Hypermutation ◽

B Cell Lymphoma ◽

Chromosomal Translocations ◽

Total N ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Genomic instability is a driving force in tumor development that can be achieved by a variety of mechanisms, such as defective chromosome segregation or inactivation of the DNA mismatch repair pathway. Although B-cell lymphomas are associated with chromosomal translocations deregulating oncogene expression, a mechanism for genome-wide instability during lymphomagenesis has long not been described. We have reported that the somatic hypermutation process (SHM), which normally targets the immunoglobulin variable region (IgV) and BCL6 genes in germinal center (GC) B-cells, functions aberrantly in >50% of diffuse large B-cell lymphoma (DLBCL), the most common type of B-cell non-Hodgkin lymphoma (Pasqualucci et al., Nature412:341, 2001). As a consequence, multiple somatic mutations are introduced into the 5′ region of genes that do not represent physiologic SHM targets, including known proto-oncogenes such as PIM1, PAX5, RhoH/TTF and cMYC. To further define the extent of this phenomenon, termed aberrant somatic hypermutation (ASHM), and to identify additional hypermutated loci of possible pathogenetic significance in DLBCL, we screened 113 genes for the presence of mutations affecting their 5′ sequences (≥1.3 Kb from the transcription start site, the target region for SHM) in 10 DLBCL cell lines. Fifteen genes (13.3%) were found to harbor a significant number of mutations (p<0.05), with 70% of the cell lines being mutated in 7 or more genes; among these, six B-cell specific loci -BCL7A, CIITA, IRF4, LRMP, NCOA3 and SIAT1- carried 9–53 mutational events distributed in 20 to 70% of the cases, corresponding to an overall mutation frequency of 0.032–0.15% (frequency in the mutated cases: 0.07–0.25%). The same genes were found hypermutated in a panel of 20 primary DLBCL biopsies, which displayed an overall mutation load of 7 to 45 distinct events/gene (total N=125). Mutations were of somatic origin, independent of chromosomal translocations to the Ig loci and were restricted to the first 1.5–2 Kb from the promoter. In addition, analogous to previously identified SHM and ASHM targets, the mutations exhibited characteristic features, including a bias for transitions over transversions, preferential hotspot (RGYW/WRCY motifs) targeting, and higher frequencies at G:C pairs. However, in contrast to physiologic SHM targets such as IgV and BCL6, none of the 4 newly identified hypermutated genes that have been analyzed so far (BCL7A, CIITA, SIAT1, LRMP) displayed significant levels of mutations in purified normal GC B-cells as well as in other B-cell malignancies. This finding indicates that these genes represent aberrant hypermutation targets resulting from a tumor-associated malfunction, possibly a loss of target specificity of the physiologic SHM process. Considering previous results and the present survey, 17 (13%) out of 130 genes investigated have been found involved in ASHM, suggesting that this aberrant activity may involve an extensive set of target genes in DLBCL. Since the mutations affect both regulatory and coding sequences of the targeted genes, aberrant SHM may represent a major contributor to the pathogenesis of this disease and may explain in part its phenotypic and clinical heterogeneity.

Download Full-text

Aberrant Somatic Hypermutation in Extranodal Marginal Zone B-Cell Lymphoma of MALT Type.

Blood ◽

10.1182/blood.v106.11.417.417 ◽

2005 ◽

Vol 106 (11) ◽

pp. 417-417 ◽

Cited By ~ 3

Author(s):

Alexander Deutsch ◽

Ariane Aigelsreiter ◽

Christine Beham-Schmid ◽

Alfred Beham ◽

Werner Linkesch ◽

...

Keyword(s):

B Cell ◽

Malt Lymphoma ◽

Marginal Zone ◽

De Novo ◽

Cell Lymphoma ◽

Somatic Hypermutation ◽

B Cell Lymphoma ◽

Chromosomal Translocations ◽

Genome Wide ◽

Balanced Translocations

Abstract Extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma) accounts for approximately 7% to 8% of all non-Hodgkin lymphomas (NHLs) being the third most frequent histological subtype. The gastrointestinal tract - particularly the stomach - is the most common site of MALT lymphoma comprising 50% of all cases, but virtually every organ may be affected by this type of lymphoma. Transformation (or de novo emergence at extranodal sites) in diffuse large B-cell lymphoma (DLBCL) occurs but - according to the WHO criteria - is considered as separate entity. The understanding of the molecular biology of MALT lymphoma has significantly improved following the recent cloning of recurrent balanced translocations such as t(11;18) or t(14;18), but a mechanism for genome-wide instability during MALT lymphomagenesis has not been described. We have reported that the somatic hypermutation process (SHM) physiologically aimed at mutating the immunoglobulin variable gene (IgV) aberrantly targets multiple proto-oncogenes in >50% of DLCBL (Pasqualucci et al., Nature412:341, 2001). Consequently, multiple mutations are introduced in the 5′ region of genes including known proto-oncogenes such as PIM-1, PAX-5, Rho/TTF and c-MYC. To further investigate whether aberrant somatic hypermutation (ASHM) also occurs in MALT lymphoma, we studied the mutation profile of these genes in 17 MALT lymphomas (6 of gastric- and 11 of nongastric origin) and 18 extranodal DLBCL (10 gastric, 8 nongastric). Mutations in one or more genes were detected in 15 of 17 (88.2%) cases of MALT lymphoma and in all of 18 (100%) cases of extranodal DLBCL. 7 of 17 (41.2%) and 15 of 18 (83.3%) carried mutations in two or more genes in the MALT- and DLBC-lymphoma group, respectively. Overall, mutations in PIM-1 occurred in 5 of 17 (29.4%) cases with MALT lymphoma and in 10 of 18 (55.5%) in extranodal DLBCL cases. For PAX-5, the distribution of mutated cases between MALT- and DLBC-lymphoma was 6 of 17 (35.3%) and 10 of 18 (55.5%), for Rho/TTF 3 of 17 (17.6%) and 8 of 18 (44.4%) and for c-MYC 9 of 17 (52.9%) and 12 of 18 (66.6%), respectively. A total of 99 sequence variants were found in 35 cases, 29 in the MALT lymphomas and 70 in extranodal DLBCL. Although the mutations were almost exclusively single base pair substitutions (n=98 ), an insertion was also present (n=1). Mutations were of somatic origins, occur independent of chromosomal translocations to the Ig loci and share features of the IgV SHM process including bias for transition over transversion, preferential hotspot (RGYW/WRCY) targeting and restriction to the first 1–2Kb from the promoter. The mean mutation frequency in mutated MALT lymphomas was with 0.045 x10−2/bp 1.7 fold lower compared to 0.08 x10−2/bp in mutated extranodal DLBCL. Further in PIM-1, PAX-5 and c-MYC some of the mutations were found to affect coding exons, leading to amino acid exchanges, thus potentially altering gene function. These data indicate that aberrant SHM is associated with extranodal DLBCL and MALT lymphoma, likewise. By mutating regulatory and coding sequences of the targeted genes and by possibly favouring chromosomal translocations ASHM may represent a major contributor to their pathogenesis. ASHM may further support a model of MALT lymphomagenesis leading from an antigen driven lesion to transformed MALT lymphoma finally evolving to overt DLBCL.

Download Full-text

miRNA Expression Profile of B-SLL Consistent with Normal Memory B Cells:BIC/miR–155 Specific Location in Proliferation Center.

Blood ◽

10.1182/blood.v110.11.2081.2081 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2081-2081

Author(s):

Miao Wang ◽

Jan-Lukas Robertus ◽

Lu-ping Tan ◽

Geert Harms ◽

Tjasso Blokzijl ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Expression Profile ◽

Mirna Expression ◽

Direct Sequencing ◽

Memory B Cells ◽

Lymphocytic Leukemia ◽

Chain Gene ◽

Mutation Status ◽

Igh Genes

Abstract Introduction: B cell Chronic Lymphocytic Leukemia (B-CLL) is characterized by the accumulation of nonproliferating mature-appearing lymphocytes in the blood, marrow, lymph nodes, and spleen. B-CLL behaves like leukemia and is found mostly in the blood. The expression of ZAP-70 and mutation status of the immunoglobulin heavy-chain gene (IgH) can serve as prognostic markers in B-CLL. ZAP-70 positive cases usually present with unmutated IgH genes and have a bad prognosis, whereas ZAP-70 negative cases mostly present with mutated IgH genes and have good prognosis. Gene expression studies of B-CLL indicated that the profile of IgH mutated and unmutated cases are similar to normal memory B cells. Several studies showed that miRNAs play important roles in pathogenesis of B-CLL and some miRNAs correlate with the prognosis in B-CLL. B-SLL is considered to be the same disease entity as CLL, but this variant is found mostly in bone marrow and the lymphatic system. The most aggressive type of B-SLL is characterized by neoplastic cells that are more responsive to B-cell receptor signaling and are characterized by proliferation centers (PCs), a potentially important site of neoplastic cell stimulation. Until now, only a few reports have been published about the ZAP-70 expression and IgH mutation status and no data are available about the microRNA expression profile. Methods: 33 B-SLL cases were retrieved from the pathology files. ZAP-70 expression was analyzed by using immunohistochemistry. IgH mutation status was determined using PCR followed by direct sequencing. Cases with homology of ≥98% with germline sequences were considered as unmutated and cases with homologies <98% as mutated. Levels of 15 miRNAs were determined by qRT-PCR using U6 as a housekeeping gene in 28 B-SLL cases with good quality RNA. As a control we also analyzed miRNA levels in normal naïve, GC and memory B cell subsets. RNA in-situ hybridization (ISH) was used to localize the most abundantly expressed miRNAs in B-SLL tissues. Results: 16 B-CLL cases were ZAP70+ with the vast majority of tumor cells staining positive and 17 were negative. Of the ZAP70+ cases 10 carried unmutated and 3 mutated IgH genes and 3 cases failed due to bad quality DNA. 14/17 ZAP-70- cases carried mutated IgH genes and 3 cases failed. miR-150, miR-21, miR-16, miR-92 and miR-155 were expressed at high levels in all B-SLL cases independent of the ZAP70 and IgH mutation status. The miRNA expression pattern in B-SLL was very similar to normal memory B cells. RNA-ISH for BIC, the primary transcript of miR-155, demonstrated the most abundant expression in the proliferation centers of B-SLL cases. Conclusion: In B-SLL there is significant correlation between ZAP-70 expression and IgH mutation status similar to B-CLL cases. miRNA expression levels in B-SLL did not correlate with ZAP-70 or IgH status. The overall expression profile is very similar to normal memory B cells. BIC/miR-155 expression is observed specifically in the proliferation center of B-SLL tissues.

Download Full-text

M17, a gene specific for germinal center (GC) B cells and a prognostic marker for GC B-cell lymphomas, is dispensable for the GC reaction in mice

Blood ◽

10.1182/blood-2005-10-4154 ◽

2006 ◽

Vol 107 (12) ◽

pp. 4849-4856 ◽

Cited By ~ 13

Author(s):

Dominik Schenten ◽

Angela Egert ◽

Manolis Pasparakis ◽

Klaus Rajewsky

Keyword(s):

Gene Expression ◽

T Cell ◽

B Cells ◽

B Cell ◽

Somatic Hypermutation ◽

Gene Expression Signature ◽

Antibody Responses ◽

B Cell Lymphomas ◽

Clinical Prognosis ◽

V Region

AbstractIn T-cell–dependent antibody responses, antigen-specific B cells undergo a phase of secondary antibody diversification in germinal centers (GCs). Somatic hypermutation (SHM) introduces mutations into the rearranged immunoglobulin (Ig) variable (V) region genes, and class-switch recombination (CSR) alters the Ig heavy (H) chain constant region. Aberrant SHM or CSR is thought to contribute to the development of GC-derived B-cell malignancies. Diffuse large B-cell lymphomas (DLBCLs) are a heterogeneous group of such GC-derived tumors. Based on their gene expression profile, DLBCLs can be divided into activated B-cell–like and GC-like subgroups. The human gene HGAL is predominantly expressed in GCs. It is also part of the gene expression signature of GC-like DLBCL, and its high expression in DLBCL has been associated with a better clinical prognosis. We have generated mice deficient of the HGAL homologue M17 in order to investigate its functional significance. The mutant animals form normal GCs, undergo efficient CSR and SHM, and mount T-cell–dependent antibody responses similar to wild-type controls. Thus, M17 is dispensable for the GC reaction, and its potential function in the pathogenesis of DLBCL remains elusive.

Download Full-text

VH Gene Analysis of Primary Cutaneous B-Cell Lymphomas: Evidence for Ongoing Somatic Hypermutation and Isotype Switching

Blood ◽

10.1182/blood.v92.10.3857.422k08_3857_3864 ◽

1998 ◽

Vol 92 (10) ◽

pp. 3857-3864 ◽

Cited By ~ 2

Author(s):

W.M. Aarts ◽

R. Willemze ◽

R.J. Bende ◽

C.J.L.M. Meijer ◽

S.T. Pals ◽

...

Keyword(s):

B Cell ◽

Somatic Hypermutation ◽

Large Cell ◽

B Cell Lymphomas ◽

Isotype Switching ◽

Variable Heavy ◽

Vh Gene ◽

Vh Genes ◽

Hodgkin's Lymphomas ◽

Center Cell

Primary cutaneous B-cell lymphomas are B-cell non-Hodgkin’s lymphomas that arise in the skin. The major subtypes discerned are follicle center cell lymphomas, immunocytomas (marginal zone B-cell lymphomas), and large B-cell lymphomas of the leg. In this study, we analyzed the variable heavy chain (VH) genes of 7 of these lymphomas, ie, 4 follicle center cell lymphomas (diffuse large-cell lymphomas) and 3 immunocytomas. We show that all these lymphomas carry heavily mutated VH genes, with no obvious bias in VH gene usage. The low ratios of replacement versus silent mutations observed in the framework regions of 5 of the 7 lymphomas suggest that the structure of the B-cell antigen receptor was preserved, as in normal B cells that are selected for antibody expression. Moreover, evidence for ongoing mutation was obtained in 3 immunocytomas and in one lymphoma of large-cell type. In addition, in 1 immunocytoma, both IgG- and IgA-expressing clones were found, indicative of isotype switching. Our data provide insight into the biology of primary cutaneous B-cell lymphomas and may be of significance for their classification.

Download Full-text

Potent germline-like monoclonal antibodies: Rapid identification of promising candidates for antibody-based antiviral therapy

Antibody Therapeutics ◽

10.1093/abt/tbab008 ◽

2021 ◽

Author(s):

Xiaoyi Zhu ◽

Fei Yu ◽

Yanling Wu ◽

Tianlei Ying

Keyword(s):

Monoclonal Antibodies ◽

Rational Design ◽

Large Scale ◽

Molecular Mechanisms ◽

Viral Infections ◽

Somatic Hypermutation ◽

Affinity Maturation ◽

Human Mabs

Abstract Recent years, fully human monoclonal antibodies (mAbs) are making up an increasing share of the pharmaceutical market. However, to improve affinity and efficacy of antibodies, many somatic hypermutation could be introduced during affinity maturation, which cause several issues including safety and efficacy and limit their application in clinic. Here, we propose a special class of human mAbs with limited level of somatic mutations, referred to as germline-like mAbs. Remarkably, germline-like mAbs could have high affinity and potent neutralizing activity in vitro and in various animal models, despite lacking of extensive affinity maturation. Furthermore, the germline nature of these mAbs implies that they exhibit lower immunogenicity and can be elicited relatively fast in vivo compared with highly somatically mutated antibodies. In this review, we summarize germline-like mAbs with strong therapeutic and protection activity against various viruses that caused large-scale outbreaks in the last decade, including influenza virus H7N9, Zika virus (ZIKV), Dengue virus (DENV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We also illustrate underlying molecular mechanisms of these germline-like antibodies against viral infections from the structural and genetic perspective, thus providing insight into further development as therapeutic agents for treatment of infectious diseases and implication for rational design of effective vaccines.

Download Full-text

Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma

Blood ◽

10.1182/blood-2002-11-3387 ◽

2003 ◽

Vol 101 (8) ◽

pp. 2914-2923 ◽

Cited By ~ 187

Author(s):

Laura Pasqualucci ◽

Anna Migliazza ◽

Katia Basso ◽

Jane Houldsworth ◽

R. S. K. Chaganti ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Somatic Hypermutation ◽

B Cell Lymphoma ◽

Chromosomal Translocations ◽

Regulatory Sequences ◽

Large B Cell Lymphoma ◽

Noncoding Exon ◽

Functional Consequences ◽

Large B Cell

Abstract The BCL6 proto-oncogene encodes a transcriptional repressor whose expression is deregulated by chromosomal translocations in approximately 40% of diffuse large B-cell lymphomas (DLBCLs). The BCL6 regulatory sequences are also targeted by somatic hypermutation in germinal center (GC) B cells and in a fraction of all GC-derived lymphomas. However, the functional consequences of these mutations are unknown. Here we report that a subset of mutations specifically associated with DLBCL causes deregulated BCL6 transcription. These mutations affect 2 adjacent BCL6 binding sites located within the first noncoding exon of the gene, and they prevent BCL6 from binding its own promoter, thereby disrupting its negative autoregulatory circuit. These alterations were found in approximately 16% of DLBCLs devoid of chromosomal translocations involving the BCL6 locus, but they were not found in normal GC B cells. This study establishes a novel mechanism for BCL6 deregulation and reveals a broader involvement of this gene in DLBCL pathogenesis.

Download Full-text