scholarly journals Absence of missense mutations in activated c-myc genes in avian leukosis virus-induced B-cell lymphomas.

1988 ◽  
Vol 8 (6) ◽  
pp. 2659-2663 ◽  
Author(s):  
M Hahn ◽  
W S Hayward
Keyword(s):  
B Cell ◽  
Gene Product ◽  
Primary Structure ◽  
Avian Leukosis Virus ◽  
Nucleotide Sequences ◽  
Missense Mutations ◽  
B Cell Lymphomas ◽  
Altered Expression

We have determined the nucleotide sequences of two independent DNA clones which contained the activated c-myc genes from avian leukosis virus-induced B-cell lymphomas. Neither of these c-myc genes contained missense mutations. This strongly supports the notion that the c-myc proto-oncogene in avian leukosis virus-induced B-cell lymphomas can be oncogenically activated by altered expression of the gene without a change in the primary structure of the gene product.

Absence of missense mutations in activated c-myc genes in avian leukosis virus-induced B-cell lymphomas

1988 ◽  
Vol 8 (6) ◽  
pp. 2659-2663
Author(s):  
M Hahn ◽  
W S Hayward
Keyword(s):  
B Cell ◽  
Gene Product ◽  
Primary Structure ◽  
Avian Leukosis Virus ◽  
Nucleotide Sequences ◽  
Missense Mutations ◽  
B Cell Lymphomas ◽  
Altered Expression

We have determined the nucleotide sequences of two independent DNA clones which contained the activated c-myc genes from avian leukosis virus-induced B-cell lymphomas. Neither of these c-myc genes contained missense mutations. This strongly supports the notion that the c-myc proto-oncogene in avian leukosis virus-induced B-cell lymphomas can be oncogenically activated by altered expression of the gene without a change in the primary structure of the gene product.

scholarly journals Selection for avian leukosis virus integration sites determines the clonal progression of B-cell lymphomas

2017 ◽  
Vol 13 (11) ◽  
pp. e1006708 ◽  
Author(s):  
Sanandan Malhotra ◽  
Shelby Winans ◽  
Gary Lam ◽  
James Justice ◽  
Robin Morgan ◽  
...  
Keyword(s):  
B Cell ◽  
Avian Leukosis Virus ◽  
B Cell Lymphomas ◽  
Integration Sites ◽  
Selection For ◽  
Virus Integration ◽  
Clonal Progression

scholarly journals Common Viral Integration Sites Identified in Avian Leukosis Virus-Induced B-Cell Lymphomas

mBio ◽  
2015 ◽  
Vol 6 (6) ◽  
Author(s):  
James F. Justice ◽  
Robin W. Morgan ◽  
Karen L. Beemon
Keyword(s):  
B Cell ◽  
High Throughput ◽  
High Throughput Sequencing ◽  
Consensus Sequence ◽  
B Cell Lymphoma ◽  
Avian Leukosis Virus ◽  
B Cell Lymphomas ◽  
Genome Wide ◽  
Integration Sites

ABSTRACTAvian leukosis virus (ALV) induces B-cell lymphoma and other neoplasms in chickens by integrating within or near cancer genes and perturbing their expression. Four genes—MYC,MYB,Mir-155, andTERT—have previously been identified as common integration sites in these virus-induced lymphomas and are thought to play a causal role in tumorigenesis. In this study, we employ high-throughput sequencing to identify additional genes driving tumorigenesis in ALV-induced B-cell lymphomas. In addition to the four genes implicated previously, we identify other genes as common integration sites, includingTNFRSF1A,MEF2C,CTDSPL,TAB2,RUNX1,MLL5,CXorf57, andBACH2. We also analyze the genome-wide ALV integration landscapein vivoand find increased frequency of ALV integration near transcriptional start sites and within transcripts. Previous work has shown ALV prefers a weak consensus sequence for integration in cultured human cells. We confirm this consensus sequence for ALV integrationin vivoin the chicken genome.IMPORTANCEAvian leukosis virus induces B-cell lymphomas in chickens. Earlier studies showed that ALV can induce tumors through insertional mutagenesis, and several genes have been implicated in the development of these tumors. In this study, we use high-throughput sequencing to reveal the genome-wide ALV integration landscape in ALV-induced B-cell lymphomas. We find elevated levels of ALV integration near transcription start sites and use common integration site analysis to greatly expand the number of genes implicated in the development of these tumors. Interestingly, we identify several genes targeted by viral insertions that have not been previously shown to be involved in cancer.

scholarly journals Shared and Distinct Genetic Features in Human and Canine B-Cell Lymphomas

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3509-3509
Author(s):  
Tiana Hillman ◽  
Matthew Cheung ◽  
Bruno M. Grande ◽  
Kevin R Bushell ◽  
Sarah E. Arthur ◽  
...  
Keyword(s):  
B Cell ◽  
Burkitt Lymphoma ◽  
B Cell Lymphoma ◽  
Driver Mutations ◽  
Missense Mutations ◽  
B Cell Lymphomas ◽  
Important Distinction ◽  
Dna Library ◽  
Genetic Features ◽  
Human B Cell

Abstract Introduction Animal models of human cancers are an important tool for the development and preclinical evaluation of new treatments. Canine B-cell lymphoma (cBCL) is an appealing alternative to murine preclinical models due to its frequent, spontaneous incidence and its clinical and histological similarity to human B-cell non-Hodgkin lymphoma (NHL). The potential utility of cBCL as a veterinary model of human B-cell lymphomas would be bolstered by a more complete understanding of the genetic features found in cBCL. Methods To study the genetics of cBCL, we obtained fresh frozen and matched plasma/serum from 86 patients from the Canine Comparative Oncology Genomic Consortium(CCOGC) with 65 confirmed as B-cell lymphomas by immunophenotyping. Tumor DNA was prepared into libraries using the QIAseq FX DNA Library Kit (Qiagen). Plasma and serum DNA was prepared into libraries using the NebNext Ultra II DNA Library Prep Kit. Targeted hybridization enrichment was performed on the libraries using our custom baits and sequencing reads were aligned to canFam3.1 using Geneious and each mutation was visually confirmed. Variants were annotated with Variant Effect Predictor and human-dog pairwise alignments were extracted from Ensembl to identify the orthologous human amino acid for all canine variants. Results Our analysis confirmed the previously reported high frequency of mutations in TRAF3 and FBXW7. We also observed mutations in POT1, TP53, and SETD2 at similar frequencies to those reported in previous studies. DDX3X was mutated in 20% of cases, which is substantially higher than previously reported. MYC mutations were also more frequent (13%) than has been previously described in cBCL. In human lymphomas, MYC is commonly deregulated by translocation to a potent enhancer and these events are often associated with point mutations in MYC that are induced by aberrant somatic hypermutation (aSHM). Interestingly, we identified a more focal pattern of MYC mutations in cBCL that implies they do not result from aSHM and are likely functional. This finding implicates the conserved MYC phosphodegron sequence, a motif commonly mutated among additional aSHM-associated mutations, as the target of bona fide driver mutations in both human and cBCLs. Mutations in FBXW7 primarily affected the substrate recognition domain responsible for MYC degradation. The observation that MYC and FBXW7 mutations did not co-occur in any canine patient is consistent with the notion that FBXW7 mutations operate as an alternative path to MYC stabilization which is not frequently observed in human NHL. DDX3X was one of the most frequently mutated genes in our cohort (20%). DDX3X mutations are common in human Burkitt lymphoma and, though less abundant in hDLBCL, tend to be observed in samples with MYC translocations. In Burkitt lymphoma, these mutations display a sex-specific pattern, wherein females show mainly missense mutations, while males are affected by loss-of-function mutations. Interestingly, all DDX3X mutations in cBCL are missense variants and are presumed to be dominant acting. This lack of sex difference in DDX3X mutations is an important distinction between human and canine B-cell lymphomas that warrants further exploration. Conclusions Our study has revealed key differences in the mutational profiles of canine and human B-cell lymphomas and provides an impetus for enhanced genomic characterization of canine lymphomas as a model for human NHL, particularly in clinical trial settings. Disclosures Grande: Sage Bionetworks: Current Employment. Alcaide: GA Diagnostics AB: Current Employment. Morin: Celgene: Consultancy; Foundation for Burkitt Lymphoma Research: Membership on an entity's Board of Directors or advisory committees; Epizyme: Patents & Royalties. Coyle: Allakos, Inc.: Consultancy.

Multiple proto-oncogene activations in avian leukosis virus-induced lymphomas: evidence for stage-specific events

1989 ◽  
Vol 9 (6) ◽  
pp. 2657-2664 ◽  
Author(s):  
B E Clurman ◽  
W S Hayward
Keyword(s):  
B Cell ◽  
Tumor Progression ◽  
Avian Leukosis Virus ◽  
Viral Integration ◽  
B Cell Lymphomas ◽  
Late Stages

We have examined avian leukosis virus-induced B-cell lymphomas for multiple, stage-specific oncogene activations. Three targets for viral integration were identified: c-myb, c-myc, and a newly identified locus termed c-bic. The c-myb and c-myc genes were associated with different lymphoma phenotypes. The c-bic locus was a target for integration in one class of lymphomas, usually in conjunction with c-myc activation. The data indicate that c-myc and c-bic may act synergistically during lymphomagenesis and that c-bic is involved in late stages of tumor progression.

scholarly journals Bclw Overexpression Predicts Aggressive Disease in B-Cell Lymphomas

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-29
Author(s):  
Amanda McBride ◽  
Clare M Adams ◽  
Ramkrishna Mitra ◽  
Christine M Eischen
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Low Grade ◽  
B Cell Lymphomas ◽  
Altered Expression ◽  
Cox Regression Analysis ◽  
Aggressive Disease ◽  
Aggressive B Cell Lymphoma

B-cell lymphomas encompass a phenotypically and genetically heterogenous subgroup within hematologic malignancies. Despite this heterogeneity, the ability to evade apoptosis is a unifying feature across B-cell lymphomas, and alterations within the Bcl-2 family of apoptosis regulatory proteins is a key mechanism for this evasion. While overexpression of the anti-apoptotic Bcl-2 family member BCL2 has been widely described in multiple B-cell lymphomas, altered expression of other anti-apoptotic proteins within this family, including BCLX, MCL1, A1 and, in particular, BCLW has been under-investigated. This is highlighted by clinical trials of the BCL2 inhibitor, venetoclax, which found poor single agent activity in B-cell lymphomas that were thought to be highly BCL2-dependent. Therefore, we investigated the contributions of anti-apoptotic Bcl-2 proteins in B-cell lymphomas. Analysis of gene expression profiling datasets of patient samples of major B-cell lymphoma subtypes as compared to normal B-cells demonstrated differential overexpression of anti-apoptotic Bcl-2 proteins, with BCL2, BCLX and BCLW being significantly overexpressed in multiple B-cell lymphoma subtypes. Focusing on aggressive B-cell lymphoma subtypes, BCLW was consistently overexpressed across all major B-cell lymphoma subtypes. Notably, BCLW overexpression was maintained in high grade follicular lymphoma compared to low grade, whereas BCL2 levels decreased as grade increased. These findings indicate that BCLW overexpression is selected for in more aggressive B-cell lymphoma subtypes. BCLW overexpression in aggressive B-cell lymphoma cell lines conferred resistance to the non-specific BH3 mimetic navitoclax as well as to venetoclax. Further, analysis of diffuse large B-cell lymphoma (DLBCL) cell lines demonstrated that the combination of high BCLW/low BCL2 in GCB DLBCL and high BCLW/moderate BCL2 in non-GCB DLBCL is also associated with decreased navitoclax sensitivity, suggesting that high BCLW may confer treatment resistance. In accordance with this, analysis of patient outcomes in DLBCL demonstrates that patients exhibiting high BCLW levels with low BCL2 levels have poorer survival than those with low BCLW. Moreover, Cox regression analysis showed BCLW was an independent determinant of overall survival in DLBCL. Together, our results indicate that BCLW predicts for more aggressive disease in B-cell lymphomas and increased resistance to therapy. Disclosures Eischen: AbbVie Inc.:Research Funding.

Classification of Highly Proliferative B Cell Lymphomas Using Differential Expression of cMYT Target Genes.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2030-2030
Author(s):  
S. L. Barrans ◽  
S. J.M. O’Connor ◽  
A. C. Rawstron ◽  
J. Allan ◽  
R. G. Owen ◽  
...  
Keyword(s):  
B Cell ◽  
Expression Profiles ◽  
Pearson Correlation ◽  
Surrogate Marker ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
High Dose ◽  
Alternative Mechanism ◽  
B Cell Lymphomas ◽  
Altered Expression

Abstract B cell lymphomas with 100% Ki67 expression, represent a spectrum of disease incorporating Burkitt Lymphoma (BL). The currently recruiting MRC (UK) LY10 trial aims to determine the efficacy of CODOX-M/IVAC in adult BL. Due to the unfeasibility of demonstrating cMYC rearrangement prior to trial entry, 100% Ki67 is being used to define trial eligibility. The purpose of this study is to evaluate the heterogeneity of tumors selected on this basis, and to determine the effectiveness of 100% Ki67 as a surrogate marker for cMYC deregulation. To date we have immunophenotypic and FISH data on tumors from 145 patients. 93 cases have 100% Ki67 and are eligible for the trial. 62/93 (66.67%) cases were found to have a BL-specific phenotype (defined as CD20+, CD10+, BCL6+, BCL2−, P53+P21- and 100% cell cycle fraction) and of these 44 (71%) have rearrangement of cMYC. Rearrangement of cMYC was exclusive to cases with a BL phenotype, however 18/62 cases express the phenotype with no evidence of cMYC rearrangement. The remaining cases were GC- or activated-DLBCL. To test the hypothesis that cMYC may be deregulated by a mechanism other than gene rearrangement in cases with a BL-Phenotype, we have compared the gene expression profiles of samples expressing a BL-phenotype, but lacking a cMYC rearrangement (BL-Phen), with typical BL cases with rearranged cMYC (BLt), using Affymetrix Human U133 plus 2.0 chips. Due to the high levels of apoptosis in these tumors, cases with fresh material to extract sufficient RNA are rare, and only 8 cases were suitable for analysis. These were split into 3 groups: BLt (3); BL-Phen (3) and 2 DLBCL with 100% Ki67 but no other features of BL. A condition tree clustering algorithm was produced using GeneSpring v6.1 and correlation of the related samples was determined by Pearson correlation (P). In addition, a sub-analysis was performed on 33 genes reported to be downstream targets of cMYC. Using this approach, the 3 BLt cases clustered, as did the 3 BL-Phen cases, however comparison between groups showed a negative association (P= −0.3), suggesting that, although the phenotype is identical to BL, the molecular pathogenesis of BL-Phen cases does not involve deregulation of cMYC. A >3 fold increase in cMYC expression was found in the BLt compared to the BL-Phen group, and several genes, including nucleolin, ornithine decarboxylase 1, eukaryotic translation initiation factor 4E, carbamoyl-phosphate synthetase 2, high mobility group AT-hook 1, transferrin receptor and branched chain aminotransferase 1, were differentially expressed in BLt compared to BL-Phen cases. Interestingly, one of the non-BL-Phen samples had similar expression of cMYC and downstream genes as the BLt cases, suggesting cMYC activation by an alternative mechanism in this case. In conclusion, B-cell lymphomas with 100% Ki67 are a heterogeneous group of tumors, in which 47% are typical BL as defined by phenotype and cMYC rearrangement. Cases with a BL-Phenotype that lack cMYC rearrangement have an expression profile suggesting that cMYC is not deregulated, and that these patients may not be suitable for treatment with high intensity chemotherapy regimens. The data presented suggests that altered expression of the cMYC targets, as described, may be a more appropriate surrogate marker for rearrangement of cMYC, and it is likely that this approach will more accurately determine which patients will benefit from high dose therapy.

Aberrant Ras Activation Associated with Functional Loss of Tnk1/Kos1 In Human B-Cell Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3159-3159
Author(s):  
Kishalay Hoare ◽  
Sarasija Hoare ◽  
Bernadette Zamora ◽  
Tammy Flagg ◽  
Ann Dongtao Fu ◽  
...  
Keyword(s):  
Fusion Protein ◽  
B Cell ◽  
Gene Product ◽  
Hematological Malignancies ◽  
Trichostatin A ◽  
B Cell Lymphoma ◽  
Allelic Loss ◽  
B Cell Lymphomas ◽  
Functional Loss ◽  
Ras Activation

Abstract Abstract 3159 Tnk1/Kos1 (Thirty-eight negative kinase/Kinase of embryonic stem cells) is the first demonstrated nonreceptor protein tyrosine kinase (PTK) to be identified as a tumor suppressor (Hoare et al.2008). The Tnk1/Kos1 knockout mice (∼80%) spontaneously develop B-cell lymphomas, specifically DLBCL, which express aberrantly high levels of Ras activity due to the loss of Tnk1/Kos1. Mechanistically the high Ras activity in the tumor tissue results from the stabilization of the RasGEF (Grb2-Sos1) complex since Ras is not found to be mutated in B-cell lymphomas. Importantly, in humans, the allelic loss of Tnk1 and/or reduced expression of Tnk1 transcripts occur in patients with DLBCL (Oncomine.org). In support of a tumorigenic mechanism, Immunohistochemical (IHC) analysis using a phospho-specific Tnk1 antibody that we developed confirms the functional loss of Tnk1 activity in DLBCL tissue. These data underscore the potential clinical relevance of Tnk1 in human hematological malignancies. Interestingly, the L540 cell line, derived from a patient with Hodgkin Lymphoma was recently reported to express a 60 Kda truncated fusion Tnk1-C17orf61 gene product (Gu et al. 2010). Although the Tnk fusion gene product is heavily tyrosine phosphorylated, we find that it possesses poor to no enzymatic activity toward the Tnk1/Kos1 substrate Grb2. This indicates that its PTK activity is possibly inhibited by steric hindrance as a result of hyper Y-phosphorylation. This is reminiscent of kinase-dead Tnk1/Kos1 and hence the truncated L540 Tnk fusion protein may function as an oncogene (Hoare et al. 2003). Interestingly, when L540 cells were exposed to 5 Aza cytidine (40μM) or Trichostatin A (100ng/ml), we find a reduction in the expression of the truncated L540 Tnk fusion protein with a concomitant increase in Ras activity (hyper Ras activation) and accumulation of cells in sub G1 phase, indicating Ras mediated induction of cell senescence and death, an event commonly observed in the over expression of several oncogenes (Serrano et al 1997; Ruggero et al, 2004). Our findings may therefore, point the way to designing a novel and effective therapy that may prevent the progression of B-cell lymphomas associated with abnormal expression of mutated Tnk1. Importantly, since Ras is infrequently mutated to oncogenic Ras in human lymphoid tumors (unlike myeloid leukemias), aberrant Ras activation in such lymphoid tumors may result from the loss of Tnk1 kinase activity due to the constitutive activation of Ras-GEF activity. These findings indicate the mechanism by which wt-Ras can be aberrantly activated to an “oncogenic” equivalent form with the loss of Tnk1 to induce and/or contribute to spontaneous tumorigenesis in hematological malignancies. Disclosures: No relevant conflicts of interest to declare.

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