106 results on '"Dave BJ"'
Search Results
2. T(14;18)-negative non-cutaneous follicular lymphoma (FL): A clinicopathological study of 59 cases
- Author
-
Shi, XL, Dave, BJ, d'Amore, Francesco Annibale, Chan, E, Jain, S, Sanger, W, Choi, WWL, Greiner, TC, Aoun, P, Weisenburger, DD, Chan, WC, and Fu, K
- Published
- 2007
3. SHARED CYTOGENETIC ABNORMALITIES IN LUNG-TUMORS AND CORRESPONDING PERIPHERAL-BLOOD LYMPHOCYTES
- Author
-
DAVE, BJ, primary, HOPWOOD, VL, additional, SPITZ, MR, additional, and PATHAK, S, additional
- Published
- 1995
- Full Text
- View/download PDF
4. NONRANDOM DISTRIBUTION OF MUTAGEN-INDUCED CHROMOSOME BREAKS IN LYMPHOCYTES OF PATIENTS WITH DIFFERENT MALIGNANCIES
- Author
-
DAVE, BJ, primary, HSU, TC, additional, HONG, WK, additional, and PATHAK, S, additional
- Published
- 1994
- Full Text
- View/download PDF
5. Molecular diagnosis of Burkitt's lymphoma.
- Author
-
Dave SS, Fu K, Wright GW, Lam LT, Kluin P, Boerma E, Greiner TC, Weisenburger DD, Rosenwald A, Ott G, Müller-Hermelink H, Gascoyne RD, Delabie J, Rimsza LM, Braziel RM, Grogan TM, Campo E, Jaffe ES, Dave BJ, and Sanger W
- Published
- 2006
6. Leukemic non-nodal cyclin D1- and SOX11-negative mantle cell lymphoma with CCND3::IGH rearrangement.
- Author
-
Tan L, Bansal G, Yeung CC, Yin J, Dave BJ, Konnick E, Wu D, and Naresh KN
- Subjects
- Adult, Humans, Cyclin D1 genetics, Biomarkers, Tumor, Cyclin D3, SOXC Transcription Factors genetics, Lymphoma, Mantle-Cell genetics, Lymphoma, Mantle-Cell pathology
- Published
- 2024
- Full Text
- View/download PDF
7. Optical Genome Mapping Helps to Identify BCR::JAK2 Rearrangement Arising from Cryptic Complex Chromosomal Aberrations: A Case Report and Literature Review.
- Author
-
Vanjari N, Tang G, Toruner GA, Wang W, Thakral B, Zhao M, Dave BJ, Khoury JD, Medeiros LJ, and Tang Z
- Subjects
- Humans, In Situ Hybridization, Fluorescence, Disease Progression, Chromosome Mapping, Janus Kinase 2 genetics, Chromosome Aberrations, Myeloproliferative Disorders genetics
- Abstract
We report a case of myeloproliferative neoplasm, not otherwise specified (MPN-NOS)-transformed AML with BCR::JAK2 rearrangement. Chromosomal analysis indicated a simple abnormal karyotype 46,XY,t(7;17)(q21;q24),t(9;22)(p24;q11.2). Fluorescence in situ hybridization (FISH) using a BCR/ABL1/ASS1 probe set suggested a possible BCR rearrangement and a reflex JAK2 breakapart probe indicated JAK2 rearrangement, most likely partnered with BCR . Optical genome mapping (OGM) analysis confirmed BCR::JAK2 derived through an inv(9)(p24p13) after a t(9;22)(p13;q11.2) in this case. Due to the complexity of chromosomal aberrations, disruption and/or rearrangement of other genes such as KIF24::BCR , JAK2::KIF24/UBAP1, and CDK6:SOX9 were also identified by OGM. Although the functionality and clinical importance of these novel rearrangements were unknown, disruption of these genes might be associated with a poorer response to chemotherapy and disease progression. We also reviewed all cases with BCR::JAK2 rearrangement reported in the literature. In conclusion, a suspected t(9;22)/ BCR::JAK2 rearrangement warrants further characterization with genomic assays such as OGM, whole chromosome sequencing, and RNA sequencing to explore other gene disruptions and/or rearrangements.
- Published
- 2023
- Full Text
- View/download PDF
8. Small molecule antagonist of CXCR2 and CXCR1 inhibits tumor growth, angiogenesis, and metastasis in pancreatic cancer.
- Author
-
Prajapati DR, Molczyk C, Purohit A, Saxena S, Sturgeon R, Dave BJ, Kumar S, Batra SK, and Singh RK
- Subjects
- Humans, Animals, Mice, Cell Line, Tumor, Cell Proliferation, Apoptosis, Receptors, Interleukin-8B metabolism, Receptors, Interleukin-8A metabolism, Pancreatic Neoplasms drug therapy
- Abstract
Pancreatic cancer (PC) has a poor prognosis, and current therapeutic strategies are ineffective in advanced diseases. We and others have shown the aberrant expression of CXCR2 and its ligands in PC development and progression. Our objective for this study was to evaluate the therapeutic utility of CXCR2/1 targeting using an small molecule antagonist, SCH-479833, in different PC preclinical murine models (syngeneic or xenogeneic). Our results demonstrate that CXCR2/1 antagonist had both antitumor and anti-metastatic effects in PC. CXCR2/1 antagonist treatment inhibited tumor cell proliferation, migration, angiogenesis, and recruitment of neutrophils, while it increased apoptosis. Treatment with the antagonist enhanced fibrosis, tumor necrosis, and extramedullary hematopoiesis. Together, these findings suggest that selectively targeting CXCR2/1 with small molecule inhibitors is a promising therapeutic approach for inhibiting PC growth, angiogenesis, and metastasis., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
9. Composite Classic Hodgkin Lymphoma and Follicular Lymphoma: A Clinicopathologic Study of 22 Cases With Review of 27 Additional Cases in the Literature.
- Author
-
Huang Y, Hu S, Larson DP, Shi M, He R, Dave BJ, Greiner TC, Fu K, McPhail ED, Ketterling RP, Medeiros LJ, and Yuan J
- Subjects
- Aged, Female, Humans, Ki-1 Antigen, Lymph Nodes pathology, Male, Middle Aged, Reed-Sternberg Cells pathology, Hodgkin Disease genetics, Hodgkin Disease pathology, Lymphoma, Follicular genetics, Lymphoma, Follicular pathology
- Abstract
Composite classic Hodgkin lymphoma and follicular lymphoma (CHLFL) is a rare and poorly characterized entity. Herein, we report the clinicopathologic features of 22 cases of CHLFL from 3 institutions and we assess 27 additional cases reported in the literature. In our cohort (n=22), patients with CHLFL had a median age of 61 years and an equal male to female incidence. Most cases (95%) arose de novo with the remaining patients having a history of non-Hodgkin lymphoma. CHLFL always involved lymph nodes (100%) and most cases (95%) revealed 2 distinct areas separately diagnostic for CHL and FL. The CHL component represented a variable proportion of the overall neoplasm (5% to 90%) and was either mixed cellularity (82%) or nodular sclerosis (18%) type. The Hodgkin/Reed-Sternberg cells expressed CD30 (100%), PAX5 (100%), CD15 (62%), BCL6 (47%), BCL2 (29%), and EBER (25%), in a polymorphous inflammatory background typical of CHL. The FL component was low-grade in 55%, grade 3A in 36%, and grade 3B in 9% of cases. All 3 cases investigated by cytogenetic methods for a clonal relationship between the CHL and FL components were clonally related. These clinicopathologic features of our cohort are similar to those of cases reported in the literature. The 5-year overall survival in combined patients with CHLFL (n=49) was 48%, comparable to CHL but worse than FL in the elderly. In summary, CHLFL is a rare entity that most often occurs in older adults, involves lymph nodes, and most commonly presents de novo. In the small number of cases assessed, the CHL and FL components are usually clonally related suggesting that the CHL and FL components may share a common progenitor B-cell, likely a mutated germinal center B-cell., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
10. The Missing LNK: Evolution from Cytosis to Chronic Myelomonocytic Leukemia in a Patient with Multiple Sclerosis and Germline SH2B3 Mutation.
- Author
-
Gundabolu K, Dave BJ, Alvares CJ, Cannatella JJ, Bhatt VR, Maness LJ, Al-Kadhimi ZS, Zabad RK, and Cushman-Vokoun AM
- Abstract
Chronic myelomonocytic leukemia (CMML) is a rare but distinct hematological neoplasm with overlapping features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). Individuals with CMML have persistent monocytosis and bone marrow dyspoiesis associated with various constitutional symptoms like fevers, unintentional weight loss, or night sweats. It is established that there is a strong association of CMML with preceding or coexisting autoimmune diseases and systemic inflammatory syndromes affecting around 20% of patients. Various molecular abnormalities like TET2, SRSF2, ASXL1, and RAS are reported in the pathogenesis of CMML, but no such mutations have been described to explain the strong association of autoimmune diseases and severe inflammatory phenotype seen in CMML. Germline mutation in SH2B adaptor protein 3 ( SH2B3 ) had been reported before to affect a family with autoimmune disorders and acute lymphoblastic leukemia. In this report, we describe the first case of a female subject with many years of preceding history of multiple sclerosis before the diagnosis of CMML. We outline the evidence supporting the pathogenic role of SH2B3 p.E395K germline mutation, connecting the dots of association between autoimmune diseases and CMML genesis., Competing Interests: Krishna Gundabolu reports receiving consulting fees from Blueprint Medicines, Novartis Pharmaceuticals, BMS company, BioMarin Pharmaceuticals, Jazz Pharmaceuticals, Bayer, Pfizer Pharmaceuticals, and research funding (institutional) for the Samus therapeutics trial and owns stock in Geron. Vijaya R Bhatt reports receiving consulting fees from Takeda, Omeros, Agios, Abbvie, Partner therapeutics, Rigel, Incyte and Partnership for Health Analytic Research, LLC (funded by Jazz), and research funding (institutional) from Jazz, Abbvie, Pfizer, Incyte, Tolero Pharmaceuticals Inc., and the National Marrow Donor Program. Drug support for a trial is provided by Oncoceutics. Zaid Al-Kadhimi owns stock in Intellia, Moderna, Bluebird, Pacific, Gilead, Novavax, and Regeneron. Rana K Zabad reports consulting fees from Genentech, Bayer, Celgene/BMS, Biogen, Sanofi, and Novartis and industry funded research with Genentech and Novartis, and is an adjudication committee member for MedDay pharmaceuticals. There are no conflicts of interest for other authors., (Copyright © 2022 Krishna Gundabolu et al.)
- Published
- 2022
- Full Text
- View/download PDF
11. Frequency, variations, and prognostic implications of chromosome 14q32 deletions in chronic lymphocytic leukemia.
- Author
-
Harris RA, Stevens JM, Pickering DL, Althof PA, Smith LM, Sanmann JN, and Dave BJ
- Subjects
- Cytogenetic Analysis, Humans, In Situ Hybridization, Fluorescence, Leukemia, Lymphocytic, Chronic, B-Cell epidemiology, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Prognosis, Retrospective Studies, Survival Rate, United States epidemiology, Biomarkers, Tumor genetics, Chromosome Deletion, Chromosomes, Human, Pair 14 genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology
- Abstract
The clinical implications of deletions within chromosome 14q32 in CLL pathogenesis remain unclear. We examined the frequency of 14q32 deletions among CLL cases by karyotype and FISH, categorized the variation using genomic microarray, and assessed the prognostic impact by time-to-first-treatment (TTFT) analysis. A 14q32 abnormality was detected in 35 % (245/698) of cases, with the majority containing a 5' partial telomeric 14q32 deletion. These deletions within the IGH variable region (35/40) ranged from 236 kb to 1.4 Mb involving FAM30A, ADAM6, LINC00226, and LINC00221. The 214 kb minimum deleted region implicated in CLL pathogenesis encompassed LINC00221. Cases with a 14q32 deletion had a shorter median TTFT compared to cases with a sole deletion/nullisomy 13q, a good prognostic indicator, and longer than cases with a sole deletion of 11q or 17p, conferring an unfavorable prognosis. This investigation underscores the importance of comprehensive testing to apprehend the implications of 14q32 deletions in CLL., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
12. Additional comments regarding IGH studies in multiple myeloma.
- Author
-
Smith SC, Althof PA, Dave BJ, and Sanmann JN
- Subjects
- Humans, Immunoglobulin Heavy Chains genetics, Translocation, Genetic, Multiple Myeloma genetics
- Published
- 2021
- Full Text
- View/download PDF
13. High-risk cytogenetics in multiple myeloma: Further scrutiny of deletions within the IGH gene region enhances risk stratification.
- Author
-
Smith SC, Althof PA, Dave BJ, and Sanmann JN
- Subjects
- Biomarkers, Tumor genetics, Genetic Testing standards, Humans, In Situ Hybridization, Fluorescence standards, Multiple Myeloma pathology, Oncogene Proteins, Fusion genetics, Sensitivity and Specificity, Gene Deletion, Genetic Testing methods, Immunoglobulin Heavy Chains genetics, In Situ Hybridization, Fluorescence methods, Multiple Myeloma genetics
- Abstract
Multiple myeloma is a clonal malignancy of plasma cells in the bone marrow. Risk stratification is partly based on cytogenetic findings that include abnormalities of the IGH locus as determined by fluorescence in situ hybridization (FISH), such as rearrangements that result in either standard-risk or high-risk gene fusions. IGH deletions have been evaluated as a group in multiple myeloma patients with respect to cumulative outcomes but have provided limited guidance. Whether these deletions have the potential to result in gene fusions and thus further stratify patients is unknown. We identified 229 IGH deletions in patients referred for plasma cell dyscrasia genetic testing over 5.5 years. Follow-up was conducted on 208 of the deletions with dual fusion FISH probes for standard-risk (IGH-CCND1) and high-risk IGH gene fusions (IGH-FGFR3, IGH-MAF, IGH-MAFB). Of all deletions identified with follow-up, 44 (21%) resulted in a gene fusion as detected by FISH, 15 (7%) of which were fusion partners associated with high-risk multiple myeloma. All fusion-positive 3'-IGH deletions (6 fusions) resulted in high-risk IGH-FGFR3 fusions. Of the 15 high-risk fusion-positive cases, eight were without other high-risk cytogenetic findings. This study is the first to evaluate the presence of IGH gene fusions upon identification of IGH deletions and to characterize the deletion locus. Importantly, these findings indicate that follow-up FISH studies with dual fusion probes should be standard of care when IGH deletions are identified in multiple myeloma., (© 2020 Wiley Periodicals, Inc.)
- Published
- 2020
- Full Text
- View/download PDF
14. Reprogramming of Ovarian Granulosa Cells by YAP1 Leads to Development of High-Grade Cancer with Mesenchymal Lineage and Serous Features.
- Author
-
Lv X, He C, Huang C, Hua G, Chen X, Timm BK, Maclin VM, Haggerty AA, Aust SK, Golden DM, Dave BJ, Tseng YA, Chen L, Wang H, Chen P, Klinkebiel DL, Karpf AR, Dong J, Drapkin RI, Rueda BR, Davis JS, and Wang C
- Abstract
Understanding the cell-of-origin of ovarian high grade serous cancer (HGSC) is the prerequisite for efficient prevention and early diagnosis of this most lethal gynecological cancer. Recently, a mesenchymal type of ovarian HGSC with the poorest prognosis among ovarian cancers was identified by both TCGA and AOCS studies. The cell-of-origin of this subtype of ovarian cancer is unknown. While pursuing studies to understand the role of the Hippo pathway in ovarian granulosa cell physiology and pathology, we unexpectedly found that the Yes-associated protein 1 (YAP1), the major effector of the Hippo signaling pathway, induced dedifferentiation and reprogramming of the ovarian granulosa cells, a unique type of ovarian follicular cells with mesenchymal lineage and high plasticity, leading to the development of high grade ovarian cancer with serous features. Our research results unveil a potential cell-of-origin for a subtype of HGSC with mesenchymal features., Competing Interests: Disclosures: The authors have no competing interests to declare
- Published
- 2020
- Full Text
- View/download PDF
15. MECOM rearrangement involving the MYC locus: Two additional patients with the rare translocation, t(3;8)(q26.2;q24), and molecular review.
- Author
-
Smith SC, Qdaisat TZS, Althof PA, Dave BJ, and Sanmann JN
- Subjects
- Aged, Chromosome Deletion, Chromosomes, Human, Pair 5 genetics, Chromosomes, Human, Pair 7 genetics, Genes, myc genetics, Humans, Male, Middle Aged, Translocation, Genetic, MDS1 and EVI1 Complex Locus Protein genetics, Myelodysplastic-Myeloproliferative Diseases genetics
- Abstract
A relatively small subset of myeloid neoplasms involve rearrangements of cytoband 3q26.2. Such rearrangements are often in response to therapy and carry a poor prognosis. The ectopic expression of MECOM is the result of such translocations. To date, thirty-three t(3;8)(q26.2;q24) cases have been reported; we contribute two patients with confirmed MECOM and MYC rearrangements. Both patients presented with pancytopenia and were diagnosed with myelodysplastic/myeloproliferative disorders. In addition to translocation t(3;8), Patient 1 possessed a derivative chromosome 5, while Patient 2 possessed monosomy 7; neither patient's clonal abnormalities resolved in follow-up studies. Of the previous 33 cases, one exhibited 5q loss, while monosomy 7 was found in fifteen. These findings contribute to the small number of reported cases with t(3;8) translocations. We also speculate about the molecular mechanisms associated with this translocation., Competing Interests: Declaration of Competing Interest All contributors have read and approved this submission; there are no conflicts of interest to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
16. Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma.
- Author
-
Heavican TB, Bouska A, Yu J, Lone W, Amador C, Gong Q, Zhang W, Li Y, Dave BJ, Nairismägi ML, Greiner TC, Vose J, Weisenburger DD, Lachel C, Wang C, Fu K, Stevens JM, Lim ST, Ong CK, Gascoyne RD, Missiaglia E, Lemonnier F, Haioun C, Hartmann S, Pedersen MB, Laginestra MA, Wilcox RA, Teh BT, Yoshida N, Ohshima K, Seto M, Rosenwald A, Ott G, Campo E, Rimsza LM, Jaffe ES, Braziel RM, d'Amore F, Inghirami G, Bertoni F, de Leval L, Gaulard P, Staudt LM, McKeithan TW, Pileri S, Chan WC, and Iqbal J
- Subjects
- Female, GATA3 Transcription Factor genetics, Gene Expression Profiling, Humans, Immunoblastic Lymphadenopathy genetics, Lymphoma, T-Cell, Peripheral classification, Male, Mutation, T-Box Domain Proteins genetics, DNA Copy Number Variations, Lymphoma, T-Cell, Peripheral genetics, Oncogenes
- Abstract
Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A /B - TP53 axis and PTEN -PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A, exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2
R172 mutation. CN losses were enriched in genes regulating PI3K-AKT-mTOR signaling in cases without IDH2 mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials., (© 2019 by The American Society of Hematology.)- Published
- 2019
- Full Text
- View/download PDF
17. Follicular large cleaved cell (centrocytic) lymphoma: an unrecognized variant of follicular lymphoma.
- Author
-
El Behery R, Laurini JA, Weisenburger DD, Smith LM, Dave BJ, Yuan J, Fu K, Chan WC, Nathwani BN, Bierman PJ, Bociek RG, Vose JM, Armitage JO, Greiner TC, and Aoun P
- Subjects
- Adult, Aged, Aged, 80 and over, B-Lymphocytes drug effects, Diagnosis, Differential, Female, Humans, Lymphocytes drug effects, Lymphoma, Follicular diagnosis, Lymphoma, Follicular mortality, Male, Middle Aged, Translocation, Genetic genetics, B-Lymphocytes pathology, Lymphocytes pathology, Lymphoma, Follicular pathology, Rituximab therapeutic use
- Abstract
The World Health Organization classification of lymphoma recommends the subdivision of follicular lymphoma (FL) into 3 grades (FL1-3) based on the average number of centroblasts per high-power field in the neoplastic follicles, but does not recognize a form of FL characterized by a predominance of large cleaved cells (centrocytes) without enough centroblasts to meet the World Health Organization criteria for FL3. We have classified such cases as follicular large cleaved cell lymphoma (FLC) and, herein, describe the pathologic and clinical features of 72 cases of this entity. The features of FLC include a follicular growth pattern with pale follicles at low magnification and frequent follicular and/or interfollicular fibrosis. Cytologically, the cells are predominantly large cleaved cells with moderately coarse to fine chromatin, absent or inconspicuous nucleoli, and small to moderate amounts of pale cytoplasm. The mean nuclear diameter of the large cleaved cells was 10.1μ, approximately twice that of small lymphocytes and similar to centroblasts. The t(14;18) was present in 83% of the cases, and a high proportion expressed BCL2 (84%), BCL6 (100%), and CD10 (88%) and had high Ki67 proliferation (81%). The clinical features of patients with FLC were similar to those with other types of FL, and survival was excellent with anthracycline-based chemotherapy plus rituximab. FLC is a variant of follicular lymphoma which should be recognized in future lymphoma classifications because the diagnosis of FLC may be important for the selection of therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
18. Modulation of p73 isoforms expression induces anti-proliferative and pro-apoptotic activity in mantle cell lymphoma independent of p53 status.
- Author
-
Hassan HM, Varney ML, Chaturvedi NK, Joshi SS, Weisenburger DD, Singh RK, and Dave BJ
- Subjects
- Apoptosis drug effects, Caspases metabolism, Cell Cycle genetics, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cell Proliferation genetics, Diclofenac pharmacology, Humans, Protein Isoforms, Tumor Protein p73 metabolism, Apoptosis genetics, Gene Expression Regulation, Neoplastic, Lymphoma, Mantle-Cell genetics, Lymphoma, Mantle-Cell metabolism, Tumor Protein p73 genetics, Tumor Suppressor Protein p53 metabolism
- Abstract
Mantle cell lymphoma (MCL) is characterized by a clinically aggressive course with frequent relapse and poor survival. The p53 pathway is frequently dysregulated and p53 status predicts clinical outcome. In this report, we investigated whether modulation of p73 isoforms by diclofenac inhibits cell growth, induces apoptosis and/or cell cycle arrest in MCL relative to p53 status. Wild-type p53 [Granta-519 and JVM-2], mutant p53 [Jeko-1 and Mino-1] expressing cells, therapy resistant cell lines, and primary human cells isolated from MCL patients were used. Overexpression of pro-apoptotic TAp73 enhanced MCL cell apoptosis. Diclofenac induced a concentration- and duration-dependent increase in TAp73, cell cycle arrest, cell death, and inhibited MCL cell growth independent of p53 status. Diclofenac treatment was associated with increased activity of caspases 3, 7, and 8 and induction of p53 transcriptional target genes. These studies demonstrate the potential for diclofenac as novel therapeutic agent in MCL independent of p53 status.
- Published
- 2016
- Full Text
- View/download PDF
19. ADA3 regulates normal and tumor mammary epithelial cell proliferation through c-MYC.
- Author
-
Griffin NI, Sharma G, Zhao X, Mirza S, Srivastava S, Dave BJ, Aleskandarany M, Rakha E, Mohibi S, Band H, and Band V
- Subjects
- Adult, Aged, Animals, Biomarkers, Tumor, Breast Neoplasms mortality, Breast Neoplasms pathology, Cell Cycle genetics, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Line, Transformed, Cell Line, Tumor, Cell Movement genetics, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p27 metabolism, Disease Models, Animal, Female, Gene Expression, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Heterografts, Humans, Kaplan-Meier Estimate, Karyotype, Mice, Middle Aged, Neoplasm Grading, Neoplasm Staging, Phenotype, Prognosis, Proportional Hazards Models, Risk Factors, Tumor Burden, Breast metabolism, Breast Neoplasms genetics, Breast Neoplasms metabolism, Epithelial Cells metabolism, Genes, myc, Transcription Factors genetics, Transcription Factors metabolism
- Abstract
Background: We have established the critical role of ADA3 as a coactivator of estrogen receptor (ER), as well as its role in cell cycle progression. Furthermore, we showed that ADA3 is predominantly nuclear in mammary epithelium, and in ER+, but is cytoplasmic in ER- breast cancers, the latter correlating with poor survival. However, the role of nuclear ADA3 in human mammary epithelial cells (hMECs), and in ER+ breast cancer cells, as well as the importance of ADA3 expression in relation to patient prognosis and survival in ER+ breast cancer have remained uncharacterized., Methods: We overexpressed ADA3 in hMECs or in ER+ breast cancer cells and assessed the effect on cell proliferation. The expression of ADA3 was analyzed then correlated with the expression of various prognostic markers, as well as survival of breast cancer patients., Results: Overexpression of ADA3 in ER- hMECs as well as in ER+ breast cancer cell lines enhanced cell proliferation. These cells showed increased cyclin B and c-MYC, decreased p27 and increased SKP2 levels. This was accompanied by increased mRNA levels of early response genes c-FOS, EGR1, and c-MYC. Analysis of breast cancer tissue specimens showed a significant correlation of ADA3 nuclear expression with c-MYC expression. Furthermore, nuclear ADA3 and c-MYC expression together showed significant correlation with tumor grade, mitosis, pleomorphism, NPI, ER/PR status, Ki67 and p27 expression. Importantly, within ER+ cases, expression of nuclear ADA3 and c-MYC also significantly correlated with Ki67 and p27 expression. Univariate Kaplan Meier analysis of four groups in the whole, as well as the ER+ patients showed that c-MYC and ADA3 combinatorial phenotypes showed significantly different breast cancer specific survival with c-MYC-high and ADA3-Low subgroup had the worst outcome. Using multivariate analyses within the whole cohort and the ER+ subgroups, the significant association of ADA3 and c-MYC expression with patients' outcome was independent of tumor grade, stage and size, and ER status., Conclusion: ADA3 overexpression enhances cell proliferation that is associated with increased expression of c-MYC. Expression patterns with respect to ADA3/c-MYC can divide patients into four significantly different subgroups, with c-MYC High and ADA3 Low status independently predicting poor survival in patients.
- Published
- 2016
- Full Text
- View/download PDF
20. Leukemic diffuse large B-cell lymphoma in a patient with myeloproliferative disorder.
- Author
-
Bhatt VR, Bociek RG, Yuan J, Fu K, Greiner TC, Dave BJ, Rajan SK, and Armitage JO
- Subjects
- Aged, Biopsy, Bone Marrow pathology, Fatal Outcome, Humans, Immunophenotyping, Lymphocytes metabolism, Lymphocytes pathology, Male, Myeloproliferative Disorders diagnosis, Positron-Emission Tomography, Primary Myelofibrosis complications, Thrombocythemia, Essential complications, Thrombocythemia, Essential diagnosis, Tomography, X-Ray Computed, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Large B-Cell, Diffuse etiology, Myeloproliferative Disorders complications
- Abstract
Essential thrombocythemia is well-known to transform to other myeloid disorders, such as leukemia; however, the risk for development of lymphoma is not as well studied. This case report discusses a 76-year-old man with a history of prefibrotic post-essential thrombocythemia myelofibrosis on ruxolitinib, who developed anemia, thrombocytopenia, and leukocytosis with peripheral blasts. Results of a bone marrow biopsy and PET and CT scans revealed stage IV leukemic diffuse large B-cell lymphoma. Several days after cessation of ruxolitinib, the patient developed fevers, hypotension, and low-grade disseminated intravascular coagulation, and subsequently developed spontaneous tumor lysis syndrome, which resulted in death. This case is unique in several aspects: it highlights the rare possibility of lymphomatous transformation of myeloproliferative disorders, an unusual presentation of lymphoma masquerading as leukemia, and the possibility of ruxolitinib withdrawal syndrome. Additionally, this case serves as a reminder that the use of novel therapies should be adopted after a thorough assessment of long-term risks, including those associated with abrupt withdrawal., (Copyright © 2015 by the National Comprehensive Cancer Network.)
- Published
- 2015
- Full Text
- View/download PDF
21. Isolated MYC cytogenetic abnormalities in diffuse large B-cell lymphoma do not predict an adverse clinical outcome.
- Author
-
Caponetti GC, Dave BJ, Perry AM, Smith LM, Jain S, Meyer PN, Bast M, Bierman PJ, Bociek RG, Vose JM, Armitage JO, Aoun P, Fu K, Greiner TC, Chan WC, Sanger WG, and Weisenburger DD
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor, Chromosome Banding, Female, Gene Rearrangement, B-Lymphocyte, Genes, bcl-2, Humans, In Situ Hybridization, Fluorescence, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse pathology, Male, Middle Aged, Neoplasm Staging, Prognosis, Proto-Oncogene Proteins c-bcl-6 genetics, Survival Analysis, Treatment Outcome, Young Adult, Chromosome Aberrations, Genes, myc, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse mortality
- Abstract
In this study, we investigated the significance of MYC, BCL2 and BCL6 gene abnormalities in a cohort of 205 diffuse large B-cell lymphoma (DLBCL) patients studied by conventional and/or fluorescence in situ hybridization cytogenetic analysis. Combining these methods, 172 cases (84%) were classified as MYC-, 17 (8%) were MYC+/BCL2-/BCL6-, and 16 (8%) were double/triple-hit lymphomas (i.e. MYC+/BCL2+, MYC+/BCL6+, or MYC+/BCL2+/BCL6+). We found a significant difference in event-free survival (EFS) among the three groups (p = 0.02), with the double/triple-hit group having the worst EFS. Patients who were MYC+, but BCL2- and BCL6-, had the best EFS. We conclude that patients with MYC+ DLBCL, but without BCL2 or BCL6 abnormalities, do not have a worse outcome when compared to those who are MYC-. However, patients with double/triple-hit DLBCL have a very poor outcome and should be treated with aggressive or novel therapies.
- Published
- 2015
- Full Text
- View/download PDF
22. Disruption of chromosomal locus 1p36 differentially modulates TAp73 and ΔNp73 expression in follicular lymphoma.
- Author
-
Hassan HM, Varney ML, Jain S, Weisenburger DD, Singh RK, and Dave BJ
- Subjects
- Apoptosis genetics, Apoptosis Regulatory Proteins genetics, Apoptosis Regulatory Proteins metabolism, Bcl-2-Like Protein 11, Cell Proliferation, DNA-Binding Proteins metabolism, Humans, In Situ Hybridization, Fluorescence, Lymphoma, Follicular metabolism, Lymphoma, Follicular pathology, Membrane Proteins genetics, Membrane Proteins metabolism, Nuclear Proteins metabolism, Protein Isoforms, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, Transcription, Genetic, Tumor Protein p73, Tumor Suppressor Proteins metabolism, Chromosome Aberrations, Chromosomes, Human, Pair 1, DNA-Binding Proteins genetics, Gene Expression Regulation, Neoplastic, Genetic Loci, Lymphoma, Follicular genetics, Nuclear Proteins genetics, Tumor Suppressor Proteins genetics
- Abstract
The TP73 gene is located at the chromosome 1p36 locus that is commonly disrupted or deleted in follicular lymphoma (FL) with poor prognosis. Therefore, we analyzed the expression of the pro-apoptotic TAp73 and anti-apoptotic ΔNp73 isoforms in cases of FL with normal or abnormal 1p36. We observed a significant increase in ΔNp73 expression and ΔNp73:TAp73 ratio, lower expression of cleaved caspase-3 and a higher frequency of Ki-67 and proliferating cell nuclear antigen (PCNA) positive cells in cases of FL with abnormal 1p36. A negative correlation between the ΔNp73:TAp73 ratio and cleaved caspase-3 expression, and a positive correlation between ΔNp73 expression and Ki-67 or PCNA, were observed. The expression of TAp73 and its pro-apoptotic transcriptional targets BIM. PUMA and NOXA were significantly lower in FL compared to reactive follicular hyperplasia. Together, our data demonstrate that 1p36 disruption is associated with increased ΔNp73 expression, decreased apoptosis and increased proliferation in FL.
- Published
- 2014
- Full Text
- View/download PDF
23. Allogeneic stem cell transplantation for Philadelphia chromosome-positive acute myeloid leukemia.
- Author
-
Bhatt VR, Akhtari M, Bociek RG, Sanmann JN, Yuan J, Dave BJ, Sanger WG, Kessinger A, and Armitage JO
- Subjects
- Adult, Antibiotics, Antineoplastic therapeutic use, Antimetabolites, Antineoplastic therapeutic use, Benzamides therapeutic use, Consolidation Chemotherapy, Cyclophosphamide therapeutic use, Cytarabine therapeutic use, Female, Graft vs Host Disease drug therapy, Humans, Idarubicin therapeutic use, Imatinib Mesylate, Induction Chemotherapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Male, Middle Aged, Piperazines therapeutic use, Protein Kinase Inhibitors therapeutic use, Pyrimidines therapeutic use, Transplantation, Homologous, Treatment Outcome, Young Adult, Hematopoietic Stem Cell Transplantation, Immunosuppressive Agents therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Philadelphia Chromosome
- Abstract
Philadelphia chromosome-positive acute myeloid leukemia (Ph(+)-AML) has a poor response to anthracycline- and cytarabine-containing regimens, high relapse rate, and dismal prognosis. Although therapy with imatinib and allogeneic stem cell transplantation (allo-SCT) is promising, relatively short follow-up limits understanding of long-term results of these therapies. This report describes the outcomes of 3 cases of Ph(+)-AML diagnosed and transplanted at the University of Nebraska Medical Center between 2004 and 2011. These patients, young and without major comorbidities, received induction therapy with 7 days of cytarabine and 3 days of idarubicin along with imatinib and consolidation therapy with high-dose cytarabine (with or without imatinib). All patients underwent 10/10 HLA-matched peripheral blood allo-SCT (sibling donor for first and third patients and unrelated donor for the second patient; all had acute graft-versus-host disease (GVHD), and the first and third patients had chronic GVHD. All patients are currently alive and experiencing complete remission at 116, 113, and 28 months after diagnosis, respectively. This report shows that the use of allo-SCT with resultant graft-versus-leukemia effect and the addition of imatinib can result in long-term remission and possible cure in some patients with Ph(+)-AML., (Copyright © 2014 by the National Comprehensive Cancer Network.)
- Published
- 2014
- Full Text
- View/download PDF
24. TP73, an under-appreciated player in non-Hodgkin lymphoma pathogenesis and management.
- Author
-
Hassan HM, Dave BJ, and Singh RK
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, DNA-Binding Proteins antagonists & inhibitors, Drug Resistance, Neoplasm genetics, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Humans, Lymphocytes metabolism, Lymphocytes pathology, Lymphoma, Non-Hodgkin drug therapy, Molecular Targeted Therapy, Nuclear Proteins antagonists & inhibitors, Tumor Protein p73, Tumor Suppressor Proteins antagonists & inhibitors, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Lymphoma, Non-Hodgkin genetics, Lymphoma, Non-Hodgkin metabolism, Nuclear Proteins genetics, Nuclear Proteins metabolism, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism
- Abstract
The TP73 gene is a member of the TP53 family with high structural homology to p53 and capable of transactivating p53 target genes. The TP73 gene locus which is highly conserved and complex, encodes for two classes of isoforms TAp73 (tumor suppressor isoforms containing the transactivation domain) and ΔNp73 (oncogenic isoforms, truncated and lacking the transactivation domain) with opposing effects. The balance between TAp73 and ΔNp73 isoforms and their harmony with other members of the TP73 family regulate various cellular responses such as apoptosis, autophagy, proliferation, and differentiation. The transcriptionally active isoforms of p73 are capable of inducing apoptosis in cancer cells independent of p53 status. Unlike p53, p73 is rarely mutated in cancers, however, the ratio of ΔNp73:TAp73 is frequently up-regulated in many carcinomas and is indicative of poor prognosis. Moreover, p73 is an important determinant of chemosensitivity and radiosensitivity, the two major treatment modalities for lymphoma. In the current review, we will provide an overview of recent progress discussing the role of TP73 in cancer, specifically addressing its relevance to lymphomagenesis, progression, therapy resistance, and its potential as a novel therapeutic target.
- Published
- 2014
- Full Text
- View/download PDF
25. Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma.
- Author
-
Bouska A, McKeithan TW, Deffenbacher KE, Lachel C, Wright GW, Iqbal J, Smith LM, Zhang W, Kucuk C, Rinaldi A, Bertoni F, Fitzgibbon J, Fu K, Weisenburger DD, Greiner TC, Dave BJ, Gascoyne RD, Rosenwald A, Ott G, Campo E, Rimsza LM, Delabie J, Jaffe ES, Braziel RM, Connors JM, Staudt LM, and Chan WC
- Subjects
- Biomarkers, Tumor genetics, DNA, Neoplasm genetics, Gene Expression Profiling, Humans, Lymphoma, Follicular mortality, Lymphoma, Follicular pathology, Lymphoma, Large B-Cell, Diffuse mortality, Lymphoma, Large B-Cell, Diffuse pathology, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide genetics, Prognosis, Survival Rate, Translocation, Genetic genetics, Cell Transformation, Neoplastic pathology, Chromosome Aberrations, Chromosomes, Human genetics, DNA Copy Number Variations genetics, Genome, Human, Lymphoma, Follicular genetics, Lymphoma, Large B-Cell, Diffuse genetics
- Abstract
Follicular lymphoma (FL), the second most common type of non-Hodgkin lymphoma in the western world, is characterized by the t(14;18) translocation, which is present in up to 90% of cases. We studied 277 lymphoma samples (198 FL and 79 transformed FL [tFL]) using a single-nucleotide polymorphism array to identify the secondary chromosomal abnormalities that drive the development of FL and its transformation to diffuse large B-cell lymphoma. Common recurrent chromosomal abnormalities in FL included gains of 2, 5, 7, 6p, 8, 12, 17q, 18, 21, and X and losses on 6q and 17p. We also observed many frequent small abnormalities, including losses of 1p36.33-p36.31, 6q23.3-q24.1, and 10q23.1-q25.1 and gains of 2p16.1-p15, 8q24.13-q24.3, and 12q12-q13.13, and identified candidate genes that may be driving this selection. Recurrent abnormalities more frequent in tFL samples included gains of 3q27.3-q28 and chromosome 11 and losses of 9p21.3 and 15q. Four abnormalities, gain of X or Xp and losses of 6q23.2-24.1 or 6q13-15, predicted overall survival. Abnormalities associated with transformation of the disease likely impair immune surveillance, activate the nuclear factor-κB pathway, and deregulate p53 and B-cell transcription factors.
- Published
- 2014
- Full Text
- View/download PDF
26. Characterization of intracellular inclusions in the urothelium of mice exposed to inorganic arsenic.
- Author
-
Dodmane PR, Arnold LL, Muirhead DE, Suzuki S, Yokohira M, Pennington KL, Dave BJ, Lu X, Le XC, and Cohen SM
- Subjects
- Animals, Cacodylic Acid toxicity, Cell Nucleus metabolism, Cell Nucleus ultrastructure, Dose-Response Relationship, Drug, Female, Inclusion Bodies metabolism, Inclusion Bodies ultrastructure, Methyltransferases deficiency, Methyltransferases genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Electron, Transmission, Mitochondria metabolism, Mitochondria ultrastructure, Time Factors, Urinary Bladder metabolism, Urinary Bladder ultrastructure, Urothelium metabolism, Urothelium ultrastructure, Cacodylic Acid analogs & derivatives, Carcinogens toxicity, Cell Nucleus drug effects, Inclusion Bodies drug effects, Mitochondria drug effects, Urinary Bladder drug effects, Urothelium drug effects
- Abstract
Inorganic arsenic (iAs) is a known human carcinogen at high exposures, increasing the incidences of urinary bladder, skin, and lung cancers. In most mammalian species, ingested iAs is excreted mainly through urine primarily as dimethylarsinic acid (DMA(V)). In wild-type (WT) mice, iAs, DMA(V), and dimethylarsinous acid (DMA(III)) exposures induce formation of intramitochondrial urothelial inclusions. Arsenite (iAs(III)) also induced intranuclear inclusions in arsenic (+3 oxidation state) methyltransferase knockout (As3mt KO) mice. The arsenic-induced formation of inclusions in the mouse urothelium was dose and time dependent. The inclusions do not occur in iAs-treated rats and do not appear to be related to arsenic-induced urothelial cytotoxicity. Similar inclusions in exfoliated urothelial cells from humans exposed to iAs have been incorrectly identified as micronuclei. We have characterized the urothelial inclusions using transmission electron microscopy (TEM), DNA-specific 4',6-diamidino-2-phenylindole (DAPI), and non-DNA-specific Giemsa staining and determined the arsenical content. The mouse inclusions stained with Giemsa but not with the DAPI stain. Analysis of urothelial mitochondrial- and nuclear-enriched fractions isolated from WT (C57BL/6) and As3mt KO mice exposed to arsenate (iAs(V)) for 4 weeks showed higher levels of iAs(V) in the treated groups. iAs(III) was the major arsenical present in the enriched nuclear fraction from iAs(V)-treated As3mt KO mice. In conclusion, the urothelial cell inclusions induced by arsenicals appear to serve as a detoxifying sequestration mechanism similar to other metals, and they do not represent micronuclei.
- Published
- 2014
- Full Text
- View/download PDF
27. B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and burkitt lymphoma: study of 39 cases.
- Author
-
Perry AM, Crockett D, Dave BJ, Althof P, Winkler L, Smith LM, Aoun P, Chan WC, Fu K, Greiner TC, Bierman P, Gregory Bociek R, Vose JM, Armitage JO, and Weisenburger DD
- Subjects
- Adult, Aged, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Burkitt Lymphoma therapy, Combined Modality Therapy, Cytogenetic Analysis, Diagnosis, Differential, Female, Humans, Immunophenotyping, Lymphoma, B-Cell classification, Lymphoma, B-Cell therapy, Lymphoma, Large B-Cell, Diffuse therapy, Male, Middle Aged, Neoplasm Staging, Treatment Outcome, Burkitt Lymphoma diagnosis, Lymphoma, B-Cell diagnosis, Lymphoma, Large B-Cell, Diffuse diagnosis
- Abstract
B-cell lymphoma, unclassifiable (B-UCL), with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, is a poorly characterized entity. Therefore, we investigated cases of B-UCL treated by the Nebraska Lymphoma Study Group (NLSG). We searched the NLSG registry for years 1985-2010 for cases of B-UCL. Immunohistochemical stains and fluorescence in situ hybridization studies for MYC, BCL2 and BCL6 gene rearrangements were performed. Among the 39 cases studied, 54% were male and 46% were female, with a median age of 69 years. The majority of patients presented with advanced-stage disease (62%) and had high (3-5) International Prognostic Index (IPI) scores (54%). The median overall survival (OS) was only 9 months and the 5-year OS was 30%. Patients with low IPI scores (0-2) had a better survival than those with high scores (3-5). The cases were genetically heterogeneous and included 11 'double-hit' lymphomas with rearrangements of both MYC and BCL2 or BCL6. None of the immunohistochemical or genetic features was predictive of survival. This B-cell lymphoma is a morphologically-recognizable entity with a spectrum of genetic abnormalities. New and better treatments are needed for this aggressive lymphoma., (© 2013 John Wiley & Sons Ltd.)
- Published
- 2013
- Full Text
- View/download PDF
28. Dietary nitrate and nitrite intake and risk of non-Hodgkin lymphoma.
- Author
-
Aschebrook-Kilfoy B, Ward MH, Dave BJ, Smith SM, Weisenburger DD, and Chiu BC
- Subjects
- Case-Control Studies, Humans, Odds Ratio, Risk, Diet, Lymphoma, Non-Hodgkin etiology, Nitrates adverse effects, Nitrites adverse effects
- Abstract
Although established risk factors such as immunodeficiency and viral infections may be responsible for a portion of cases of non-Hodgkin lymphoma (NHL), the vast majority of cases of NHL remain unexplained. The role of dietary nitrate and nitrite in NHL risk is of interest since they are precursors of N-nitroso compounds, and nitrosoureas have been shown to induce B- and T-cell lymphomas in animal studies. However, few studies have evaluated the potential association between consumption of nitrate and nitrite and NHL by subtype or chromosomal translocation status, and the results of these studies have been inconsistent. We estimated the dietary intake of nitrate and nitrite using a food frequency questionnaire in a population-based, case-control study of 348 cases and 470 controls conducted in Nebraska in 1999-2002. A non-significant excess risk of NHL was found among women who reported an intake of nitrite in the highest quartile compared to the lowest quartile (odds ratio [OR] = 1.6; 95% confidence interval [CI]: 0.8-2.9), particularly nitrite from animal sources (OR = 1.9; 95% CI: 1.0-3.4). No significant associations were observed for nitrate or nitrite by NHL subtype. Although there were some increases in risk that support the N-nitroso hypothesis, they were not significant and do not confer strong evidence of an association.
- Published
- 2013
- Full Text
- View/download PDF
29. Differences in the cytogenetic alteration profiles of diffuse large B-cell lymphoma among Chinese and American patients.
- Author
-
Chen Y, Dave BJ, Zhu X, Chan WC, Iqbal J, Sanger WG, and Fu K
- Subjects
- Adult, Aged, Aged, 80 and over, Asian People genetics, Female, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Incidence, Karyotype, Lymphoma, Large B-Cell, Diffuse ethnology, Male, Middle Aged, Proto-Oncogene Proteins c-bcl-6, White People genetics, DNA-Binding Proteins genetics, Gene Rearrangement, Genes, myc, Lymphoma, Large B-Cell, Diffuse genetics
- Abstract
To study the similarities and differences of cytogenetic alterations in diffuse large B-cell lymphoma (DLBCL) between Asian and Caucasian patients, we compared the cytogenetic profiles of Chinese and American DLBCL cases by analyzing conventional karyotypes and select fluorescence in situ hybridization (FISH) findings. We used interphase FISH analyses to determine the incidence of the t(14;18) and BCL6 and MYC rearrangements. Immunohistochemical analysis was used to categorize the lymphomas into the germinal center B-cell-like (GCB) or non-GCB-DLBCL subtypes, according to the Hans algorithm. Our data suggested that Chinese patients had cytogenetic profiles for GCB-DLBCL that differed from those of their American counterparts; specifically, the Chinese GCB patients exhibited greater frequencies of BCL6 rearrangements and gains of 1q and 11q but lower incidence of the t(14;18). Non-GCB-DLBCL in both the Chinese and American patients was characterized by recurrent gains of 3/3q and 18/18q. The incidences of both BCL6 rearrangement and t(14;18) were similar in Chinese and American non-GCB-DLBCL cases., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
30. HACE1 is a tumor suppressor gene candidate in natural killer cell neoplasms.
- Author
-
Küçük C, Hu X, Iqbal J, Gaulard P, Klinkebiel D, Cornish A, Dave BJ, and Chan WC
- Subjects
- Apoptosis genetics, Cell Cycle Checkpoints genetics, Coculture Techniques, CpG Islands genetics, DNA Methylation, DNA Mutational Analysis methods, DNA, Neoplasm genetics, Gene Deletion, Gene Expression Regulation, Neoplastic, Gene Silencing, Genes, Tumor Suppressor, Humans, Interleukin-2 immunology, Killer Cells, Natural immunology, Killer Cells, Natural pathology, Lymphocyte Activation genetics, Lymphoma, Non-Hodgkin metabolism, Lymphoma, Non-Hodgkin pathology, Tumor Cells, Cultured, Ubiquitin-Protein Ligases biosynthesis, Up-Regulation genetics, Killer Cells, Natural metabolism, Lymphoma, Non-Hodgkin genetics, Ubiquitin-Protein Ligases genetics
- Abstract
HACE1 is an E3 ubiquitin ligase located in 6q21, the genomic region frequently deleted in natural killer (NK) cell malignancies. Here, we report HACE1 as a candidate tumor suppressor gene silenced through a combination of deletion and cytosine phosphate guanine island hypermethylation. We detected deletion of HACE1 in malignant NK cell lines (6 of 9, 67%) and primary biopsies (5 of 15, 33%) by quantitative PCR, with most of the specimen showing cytosine phosphate guanine island hypermethylation in the remaining allele, leading to low mRNA transcription. The ectopic expression of HACE1 in an HACE1-null NK cell line led to apoptosis and G2/M cell cycle arrest. Moreover, HACE1 expression was up-regulated in IL-2-activated normal NK cells and NK cells cocultured with an engineered NK cell target, K562 Clone 9.mbIL21, suggesting its role in the regulation of NK cell homeostasis. In conclusion, HACE1 is another potent tumor suppressor gene located within the 6q21 region, and loss of function of multiple tumor suppressor genes within 6q21 may be a critical determinant of NK cell lymphomagenesis., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
31. Alteration/deficiency in activation-3 (Ada3) plays a critical role in maintaining genomic stability.
- Author
-
Mirza S, Katafiasz BJ, Kumar R, Wang J, Mohibi S, Jain S, Gurumurthy CB, Pandita TK, Dave BJ, Band H, and Band V
- Subjects
- Animals, Ataxia Telangiectasia Mutated Proteins, Carrier Proteins metabolism, Cell Cycle Proteins metabolism, Cell Line, Chromosomal Proteins, Non-Histone metabolism, Chromosome Aberrations, DNA Damage, DNA Repair, DNA-Binding Proteins metabolism, G1 Phase, G2 Phase, Histones metabolism, Karyotyping, Mice, Phosphorylation, Protein Serine-Threonine Kinases metabolism, Rad51 Recombinase metabolism, Radiation, Ionizing, Transcription Factors deficiency, Transcription Factors genetics, Tumor Suppressor Proteins metabolism, Tumor Suppressor p53-Binding Protein 1, Genomic Instability, Transcription Factors metabolism
- Abstract
Cell cycle regulation and DNA repair following damage are essential for maintaining genome integrity. DNA damage activates checkpoints in order to repair damaged DNA prior to exit to the next phase of cell cycle. Recently, we have shown the role of Ada3, a component of various histone acetyltransferase complexes, in cell cycle regulation, and loss of Ada3 results in mouse embryonic lethality. Here, we used adenovirus-Cre-mediated Ada3 deletion in Ada3(fl/fl) mouse embryonic fibroblasts (MEFs) to assess the role of Ada3 in DNA damage response following exposure to ionizing radiation (IR). We report that Ada3 depletion was associated with increased levels of phospho-ATM (pATM), γH2AX, phospho-53BP1 (p53BP1) and phospho-RAD51 (pRAD51) in untreated cells; however, radiation response was intact in Ada3(-/-) cells. Notably, Ada3(-/-) cells exhibited a significant delay in disappearance of DNA damage foci for several critical proteins involved in the DNA repair process. Significantly, loss of Ada3 led to enhanced chromosomal aberrations, such as chromosome breaks, fragments, deletions and translocations, which further increased upon DNA damage. Notably, the total numbers of aberrations were more clearly observed in S-phase, as compared with G₁ or G₂ phases of cell cycle with IR. Lastly, comparison of DNA damage in Ada3(fl/fl) and Ada3(-/-) cells confirmed higher residual DNA damage in Ada3(-/-) cells, underscoring a critical role of Ada3 in the DNA repair process. Taken together, these findings provide evidence for a novel role for Ada3 in maintenance of the DNA repair process and genomic stability.
- Published
- 2012
- Full Text
- View/download PDF
32. Establishment and characterization of therapy-resistant mantle cell lymphoma cell lines derived from different tissue sites.
- Author
-
Ahrens AK, Chaturvedi NK, Nordgren TM, Dave BJ, and Joshi SS
- Subjects
- Animals, Cell Line, Tumor, Chromosome Aberrations, Cyclin D1 analysis, Drug Resistance, Neoplasm, Epigenesis, Genetic, Flow Cytometry, Gene Expression Profiling, Humans, Immunophenotyping, Lymphoma, Mantle-Cell drug therapy, Lymphoma, Mantle-Cell genetics, Mice, Proto-Oncogene Proteins c-bcl-2 analysis, Tumor Microenvironment, Lymphoma, Mantle-Cell pathology
- Abstract
Mantle cell lymphoma (MCL) is a rare but aggressive form of B cell non-Hodgkin lymphoma in which therapy resistance is common. New therapeutic options have extended survival in refractory MCL but have not provided durable remission. Tools are needed to assess the molecular and genetic changes associated with therapy resistance. Therefore, therapy-resistant MCL cell lines were established from the liver, kidney and lungs of human Granta 519-bearing NOD-SCID (non-obese diabetic-severe combined immunodeficiency) mice following treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy in combination with bortezomib. The cytomorphologies, immunophenotypes, growth patterns in semi-solid agar, cytogenetic profiles and gene expression differences between these cell lines were characterized to identify major changes associated with therapy resistance. Therapy-resistant cell lines exhibit more aggressive growth patterns and markedly different gene expression profiles compared to parental Granta 519 cells. Thus, these stable therapy-resistant cell lines are useful models to further study the molecular basis of drug resistance and to identify clinically relevant molecular targets in MCL.
- Published
- 2012
- Full Text
- View/download PDF
33. Lymphoma cytogenetics.
- Author
-
Dave BJ, Nelson M, and Sanger WG
- Subjects
- Chromosome Aberrations, Disease Progression, Humans, In Situ Hybridization, Fluorescence, Lymphoma pathology, Oligonucleotide Array Sequence Analysis, Prognosis, Cytogenetics methods, Lymphoma genetics
- Abstract
Lymphomas are a heterogeneous group of neoplasms with distinct morphologic, immunologic, and cytogenetic characteristics. Overlapping morphologic and immunophenotypic features often makes accurate diagnosis difficult. Cytogenetics helps simplify the diagnostic complexities presented in transforming and progressive lymphoid malignancies. Genetic studies using technical advances such as fluorescence in situ hybridization and the newer approaches of array comparative genomic hybridization and gene expression profiling play a critical and often defining role in the diagnosis, progression, prognosis, and therapeutic stratification. This article reviews characteristic cytogenetic abnormalities in specific subtypes of lymphomas at diagnosis, disease progression, and prognosis.
- Published
- 2011
- Full Text
- View/download PDF
34. Immunostaining to identify molecular subtypes of diffuse large B-cell lymphoma in a population-based epidemiologic study in the pre-rituximab era.
- Author
-
Morton LM, Cerhan JR, Hartge P, Vasef MA, Neppalli VT, Natkunam Y, Dogan A, Dave BJ, Jain S, Levy R, Lossos IS, Cozen W, Davis S, Schenk MJ, Maurer MJ, Lynch CF, Rothman N, Chatterjee N, Yu K, Staudt LM, Weisenburger DD, and Wang SS
- Abstract
Gene expression profiling studies have distinguished diffuse large B-cell lymphomas (DLBCLs) by cell of origin, with distinct pathogenetic mechanisms and prognosis. We attempted to identify DLBCL molecular subtypes in an epidemiologic study of 214 DLBCL patients diagnosed during 1998-2000 with archival tissues to investigate etiology. Immunohistochemical staining for CD10, BCL6, LMO2, MUM1/IRF4, and BCL2 and fluorescence in situ hybridization for t(14;18) were conducted, with ≥93% blinded duplicate agreement. CD10, LMO2, and BCL2 expression was similar to previous reports (32%, 44%, and 44% of DLBCLs, respectively), but BCL6 and MUM1/IRF4 expression was lower than expected (29% and 5%, respectively). We classified 112/214 (52%) cases as germinal center B-cell-like DLBCL (GCB-DLBCL; Hans et al., Blood 2004; CD10+ or CD10-/BCL6+/MUM1-), with no difference in prognosis compared with non-GCB-DLBCL (Cox regression, P=0.48). Comparing other GCB correlates, LMO2 expression and t(14;18) were more common but not exclusive to GCB-DLBCL as defined in our study, whereas BCL2 expression did not differ between DLBCL molecular subtypes. We could not confidently identify patients with GCB-DLBCL using these immunohistochemistry-based markers on archival tissues.
- Published
- 2011
35. Risk factors for non-Hodgkin lymphoma subtypes defined by histology and t(14;18) in a population-based case-control study.
- Author
-
Chang CM, Wang SS, Dave BJ, Jain S, Vasef MA, Weisenburger DD, Cozen W, Davis S, Severson RK, Lynch CF, Rothman N, Cerhan JR, Hartge P, and Morton LM
- Subjects
- Adult, Aged, Case-Control Studies, Female, Humans, In Situ Hybridization, Fluorescence, Lymphoma, Follicular epidemiology, Lymphoma, Follicular genetics, Lymphoma, Follicular pathology, Lymphoma, Large B-Cell, Diffuse epidemiology, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse pathology, Male, Middle Aged, Prognosis, Risk Factors, United States epidemiology, Young Adult, Chromosomes, Human, Pair 14 genetics, Chromosomes, Human, Pair 18 genetics, Lymphoma, Follicular classification, Lymphoma, Large B-Cell, Diffuse classification, Translocation, Genetic
- Abstract
The t(14;18) chromosomal translocation is the most common cytogenetic abnormality in non-Hodgkin lymphoma (NHL), occurring in 70-90% of follicular lymphomas (FL) and 30-50% of diffuse large B-cell lymphomas (DLBCL). Previous t(14;18)-NHL studies have not evaluated risk factors for NHL defined by both t(14;18) status and histology. In this population-based case-control study, t(14;18) status was determined in DLBCL cases using fluorescence in situ hybridization on paraffin-embedded tumor sections. Polytomous logistic regression was used to evaluate the association between a wide variety of exposures and t(14;18)-positive (N=109) and -negative DLBCL (N=125) and FL (N=318), adjusting for sex, age, race, and study center. Taller height, more lifetime surgeries, and PCB180 exposure were associated with t(14;18)-positivity. Taller individuals (third tertile vs. first tertile) had elevated risks of t(14;18)-positive DLBCL (odds ratio [OR] = 1.8, 95% confidence interval [CI] 1.1-3.0) and FL (OR=1.4, 95%CI 1.0-1.9) but not t(14;18)-negative DLBCL. Similar patterns were seen for individuals with more lifetime surgeries (13+ vs. 0-12 surgeries; t(14;18)-positive DLBCL OR=1.4, 95%CI 0.7-2.7; FL OR=1.6, 95%CI 1.1-2.5) and individuals exposed to PCB180 greater than 20.8 ng/g (t(14;18)-positive DLBCL OR=1.3, 95%CI 0.6-2.9; FL OR=1.7, 95%CI 1.0-2.8). In contrast, termite treatment and high alpha-chlordane levels were associated with t(14;18)-negative DLBCL only, suggesting that these exposures do not act through t(14;18). Our findings suggest that putative associations between NHL and height, surgeries, and PCB180 may be t(14;18)-mediated and provide support for case-subtyping based on molecular and histologic subtypes. Future efforts should focus on pooling data to confirm and extend previous research on risk factors for t(14;18)-NHL subtypes., (Copyright © 2010 UICC.)
- Published
- 2011
- Full Text
- View/download PDF
36. 18q22.3 --> 18q23 deletion syndrome and cleft palate.
- Author
-
Eudy JD, Pickering DL, Lutz R, Platt K, Dave BJ, Olney AH, and Sanger WG
- Subjects
- Child, Comparative Genomic Hybridization, Female, Humans, Male, Pedigree, Syndrome, Chromosome Deletion, Chromosomes, Human, Pair 18 genetics, Cleft Palate genetics
- Published
- 2010
- Full Text
- View/download PDF
37. An increased frequency of 13q deletions detected by fluorescence in situ hybridization and its impact on survival in children and adolescents with Burkitt lymphoma: results from the Children's Oncology Group study CCG-5961.
- Author
-
Nelson M, Perkins SL, Dave BJ, Coccia PF, Bridge JA, Lyden ER, Heerema NA, Lones MA, Harrison L, Cairo MS, and Sanger WG
- Subjects
- Adolescent, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Burkitt Lymphoma drug therapy, Burkitt Lymphoma pathology, Child, Child, Preschool, Epidemiologic Methods, Female, Humans, In Situ Hybridization, Fluorescence, Infant, Male, Neoplasm Staging, Prognosis, Treatment Outcome, Young Adult, Burkitt Lymphoma genetics, Chromosome Deletion, Chromosomes, Human, Pair 13 genetics
- Abstract
Burkitt lymphoma (BL), an aggressive B-cell malignancy, is often curable with short intensive treatment regiments. Nearly all BLs contain rearrangements of the MYC/8q24 region; however, recent cytogenetic studies suggest that certain secondary chromosomal aberrations in BL correlate with an adverse prognosis. In this multi-centre study, the frequency and impact on clinical outcome of del(13q) and +7 in addition to MYC rearrangements as detected by fluorescence in situ hybridization (FISH) in children and adolescents with intermediate and high-risk BL registered on Children's Cancer Group study CCG-5961 were investigated. Analysis with 13q14.3 and 13q34 loci specific probes demonstrated deletions of 13q in 38/90 (42%) cases. The loss of either 13q14.3 or 13q34 alone occurred in 14% and 8% respectively, while 20% exhibited loss of both regions. Gain of chromosome 7 was observed in 7/68 (10%) cases and MYC rearrangements were detected in 84/90 (93%). Prognostic analysis controlling for known risk factors demonstrated that patients exhibiting loss of 13q, particularly 13q14.3, had a significant decrease in 5-year overall survival (77% vs. 95%, P = 0.012). These observations indicate that del(13q) occurs in childhood BL at frequencies higher than previously detected by classical cytogenetics and underscores the importance of molecular cytogenetics in risk stratification.
- Published
- 2010
- Full Text
- View/download PDF
38. Non cell-autonomous reprogramming of adult ocular progenitors: generation of pluripotent stem cells without exogenous transcription factors.
- Author
-
Balasubramanian S, Babai N, Chaudhuri A, Qiu F, Bhattacharya S, Dave BJ, Parameswaran S, Carson SD, Thoreson WB, Sharp JG, Rao M, and Ahmad I
- Subjects
- Adult Stem Cells metabolism, Animals, Cell Differentiation, Cell Line, Cell Lineage, Eye metabolism, Gene Expression Regulation, Mice, Pluripotent Stem Cells metabolism, Rats, Transcription Factors metabolism, Adult Stem Cells cytology, Cellular Reprogramming, Eye cytology, Pluripotent Stem Cells cytology
- Abstract
Direct reprogramming of differentiated cells to induced pluripotent stem (iPS) cells by ectopic expression of defined transcription factors (TFs) represents a significant breakthrough towards the use of stem cells in regenerative medicine (Takahashi and Yamanaka Cell 2006;126:663-676). However, the virus-mediated expression of exogenous transcription factors could be potentially harmful and, therefore, represents a barrier to the clinical use of iPS cells. Several approaches, ranging from plasmid-mediated TF expression to introduction of recombinant TFs (Yamanaka Cell 2009;137:13-17; Zhou, Wu, Joo et al. Cell Stem Cell 2009;4:381-384), have been reported to address the risk associated with viral integration. We describe an alternative strategy of reprogramming somatic progenitors entirely through the recruitment of endogenous genes without the introduction of genetic materials or exogenous factors. To this end, we reprogrammed accessible and renewable progenitors from the limbal epithelium of adult rat eye by microenvironment-based induction of endogenous iPS cell genes. Non cell-autonomous reprogramming generates cells that are pluripotent and capable of differentiating into functional neurons, cardiomyocytes, and hepatocytes, which may facilitate autologous cell therapy to treat degenerative diseases.
- Published
- 2009
- Full Text
- View/download PDF
39. Inherited 14q duplication and 21q deletion: a rare adjacent-2 segregation in multiple family members.
- Author
-
Dave BJ, Olney AH, Zaleski DH, Pickering DL, Becker TA, Chipman HE, and Sanger WG
- Subjects
- Abnormalities, Multiple genetics, Adult, Chromosome Deletion, Family, Female, Gene Duplication, Humans, Infant, Male, Pedigree, Chromosome Aberrations, Chromosome Disorders genetics, Chromosome Segregation genetics, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 21
- Abstract
We present a family with multiple carriers of a subtle balanced translocation t(14;21)(q21.2;q21.2) and three patients with a resultant adjacent-2 malsegregation containing a +der(14)t(14;21)(q21.2;q21.2),-21 in their chromosome complement. The initial study was performed when a 2-month-old female was referred to genetics clinic for evaluation of developmental delay, growth retardation, and failure to thrive. Physical findings included prominent eyes, micrognathia, prominent and simple external ears, camptodactyly, contractures of the wrists, ankles, and hips, hypoplasia of the corpus callosum, prominent atria and occipital horns, cerebellopontine hypoplasia; and small atrial septal defect. High resolution chromosomes showed an extra band on the proximal 21q and fluorescence in situ hybridization (FISH) demonstrated only one signal for the centromere of 21. Karyotypes of the parents and grandparents revealed that the mother and maternal grandfather were carriers of a balanced translocation, and the propositus contained an unbalanced chromosome complement with partial duplication of proximal 14q and partial deletion of proximal 21q. Investigations performed on an institutionalized maternal aunt revealed identical karyotypic abnormalities as in the propositus. More recently, array comparative genomic hybridization (aCGH) on a subsequent child with multiple congenital anomalies further out in the extended family allowed for more accurate identification of the breakpoints. Our investigation includes analysis on a total of 11 family members spanning three generations. Among those investigated, there were no living members with other possible consequential unbalanced translocations or with adjacent-2 segregation resulting in -14,+der(21). Chromosome rearrangements require FISH and aCGH studies for accurate identification and elucidation of the abnormality and breakpoints.
- Published
- 2009
- Full Text
- View/download PDF
40. t(14;18)-negative follicular lymphomas are associated with a high frequency of BCL6 rearrangement at the alternative breakpoint region.
- Author
-
Gu K, Fu K, Jain S, Liu Z, Iqbal J, Li M, Sanger WG, Weisenburger DD, Greiner TC, Aoun P, Dave BJ, and Chan WC
- Subjects
- Adult, Aged, Aged, 80 and over, Chromosome Breakage, Chromosomes, Human, Pair 14 genetics, Chromosomes, Human, Pair 18 genetics, Female, Humans, In Situ Hybridization, Fluorescence, Lymphoma, Large B-Cell, Diffuse genetics, Male, Middle Aged, Proto-Oncogene Proteins c-bcl-6, Translocation, Genetic genetics, DNA-Binding Proteins genetics, Gene Rearrangement, Lymphoma, Follicular genetics
- Abstract
A frequent chromosomal translocation in mature B-cell non-Hodgkin lymphoma affects band 3q27 and results in the deregulation of the B-cell lymphoma 6 (BCL6) gene. Two breakpoint clusters have been described thus far, the major breakpoint region (MBR) and an alternative breakpoint region (ABR) that is located 245-285 kb 5' to BCL6. Translocation at the MBR predominates in diffuse large B-cell lymphoma, whereas translocation at the ABR is reported to be frequently associated with grade 3B follicular lymphoma. However, translocation at the ABR has not been studied in a large series of follicular lymphomas, particularly t(14;18)-negative follicular lymphomas. Therefore, we studied BLC6 rearrangements at the MBR and ABR by using break-apart fluorescence in situ hybridization (FISH) probes in 142 cases of follicular lymphomas, including 63 t(14;18)-negative and 79 t(14;18)-positive cases. Conventional cytogenetic (karyotype) analysis was also performed in 58 of the 63 t(14;18)-negative cases. BCL6 rearrangement was found in 26% of t(14;18)-negative and 19% of t(14;18)-positive follicular lymphoma. t(14;18)-negative cases showed a high frequency of rearrangement at the ABR (12%) with an ABR/MBR ratio of 0.86, compared with only 5% with an ABR/MBR ratio of 0.36 in the t(14;18)-positive cases. BCL6 rearrangements were found in all grades of follicular lymphoma but were most frequent in grade 3 t(14;18)-negative follicular lymphoma (60%). FISH analysis had a higher sensitivity for detecting BCL6 rearrangements than conventional cytogenetics. In conclusion, BCL6 rearrangements occur at a similar frequency in t(14;18)-negative follicular lymphoma and diffuse large B-cell lymphoma. However, t(14;18)-negative follicular lymphoma appears to have a higher frequency of rearrangement at the ABR compared with t(14;18)-positive follicular lymphoma and diffuse large B-cell lymphoma. Therefore, it is important to perform FISH analysis with ABR to determine possible involvement of BCL6 rearrangement in follicular lymphoma, especially in t(14;18)-negative cases.
- Published
- 2009
- Full Text
- View/download PDF
41. Biotinylation of histones represses transposable elements in human and mouse cells and cell lines and in Drosophila melanogaster.
- Author
-
Chew YC, West JT, Kratzer SJ, Ilvarsonn AM, Eissenberg JC, Dave BJ, Klinkebiel D, Christman JK, and Zempleni J
- Subjects
- Adult, Animals, Biotin administration & dosage, Biotinylation, Carbon-Nitrogen Ligases antagonists & inhibitors, Carbon-Nitrogen Ligases genetics, Carbon-Nitrogen Ligases metabolism, Cell Line, Chromosome Aberrations, Cytosine metabolism, DNA Methylation, Dietary Supplements, Drosophila melanogaster, Epigenesis, Genetic, Female, Humans, Jurkat Cells, Male, Mammary Tumor Virus, Mouse drug effects, Mammary Tumor Virus, Mouse physiology, Mice, Middle Aged, Repressor Proteins chemistry, Repressor Proteins metabolism, Terminal Repeat Sequences, Transcription, Genetic drug effects, Virus Assembly drug effects, Young Adult, DNA Transposable Elements, Histones chemistry, Histones metabolism
- Abstract
Transposable elements such as long terminal repeats (LTR) constitute approximately 45% of the human genome; transposition events impair genome stability. Fifty-four promoter-active retrotransposons have been identified in humans. Epigenetic mechanisms are important for transcriptional repression of retrotransposons, preventing transposition events, and abnormal regulation of genes. Here, we demonstrate that the covalent binding of the vitamin biotin to lysine-12 in histone H4 (H4K12bio) and lysine-9 in histone H2A (H2AK9bio), mediated by holocarboxylase synthetase (HCS), is an epigenetic mechanism to repress retrotransposon transcription in human and mouse cell lines and in primary cells from a human supplementation study. Abundance of H4K12bio and H2AK9bio at intact retrotransposons and a solitary LTR depended on biotin supply and HCS activity and was inversely linked with the abundance of LTR transcripts. Knockdown of HCS in Drosophila melanogaster enhances retrotransposition in the germline. Importantly, we demonstrated that depletion of H4K12bio and H2AK9bio in biotin-deficient cells correlates with increased production of viral particles and transposition events and ultimately decreases chromosomal stability. Collectively, this study reveals a novel diet-dependent epigenetic mechanism that could affect cancer risk.
- Published
- 2008
- Full Text
- View/download PDF
42. Clonal evolution in t(14;18)-positive follicular lymphoma, evidence for multiple common pathways, and frequent parallel clonal evolution.
- Author
-
d'Amore F, Chan E, Iqbal J, Geng H, Young K, Xiao L, Hess MM, Sanger WG, Smith L, Wiuf C, Hagberg O, Fu K, Chan WC, and Dave BJ
- Subjects
- Chromosome Aberrations, Clone Cells, Disease Progression, Humans, Kaplan-Meier Estimate, Karyotyping, Lymphoma, Follicular mortality, Translocation, Genetic, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 18, Lymphoma, Follicular genetics, Lymphoma, Follicular pathology
- Abstract
Purpose: Follicular lymphoma typically has acquired a t(14;18) translocation, but subsequent additional cytogenetic abnormalities contribute to disease progression. The main aims of the study are to (a) identify the frequency and temporal sequence of cytogenetic events in t(14;18)-positive follicular lymphoma, (b) determine if there are specific pathways in the evolution of follicular lymphoma, (c) determine the clonal divergence in cases with sequential biopsies or multiple clones from a single biopsy, and (d) determine the association of genetic imbalances with clinical outcome., Experimental Design: All cases with a histologically confirmed diagnosis of follicular lymphoma and cytogenetic analysis showing t(14;18)(q32;q21) were included. The karyotypes were reviewed and cytogenetic data were entered into a relational database for further computational analysis; 418 biopsies from 360 follicular lymphoma patients including 43 sequential biopsies were analyzed., Results: Of the cases with only one or two genomic imbalances, the most frequent chromosomal imbalances were +7, del(6q), +der(18)t(14;18), +18, and +X. These abnormalities were also among the most frequent ones encountered when all karyotypes were analyzed. Cytogenetically abnormal clones in the same (26%) and sequential biopsies (63%) often showed divergence of genetic alterations. Balanced translocations other than the t(14;18) were uncommon events, but chromosomal breaks involving 14q32, 18q21, 1p36, 1q21, 10q22, 10q24, and a large cluster at 6q occurred relatively frequently. del(6q), +5, +19, and +20 were associated with poorer overall survival, and del(17p) was associated with poorer event-free survival. Lower-grade tumors (1 and 2) were associated with fewer imbalances., Conclusion: Our analysis suggested that +der(18)t(14;18) may be an entry point to a distinct pathway of genetic evolution in follicular lymphoma. The other common early events appeared to provide multiple entry points, and they might cooperate in the pathogenesis and progression of the follicular lymphoma. Cytogenetically abnormal clones from same patients often showed divergence of genetic alterations, suggesting that parallel evolution from precursor clones are frequent events. This study provides the framework for further analysis of genetic pathways of tumor progression.
- Published
- 2008
- Full Text
- View/download PDF
43. Dietary factors and risk of t(14;18)-defined subgroups of non-Hodgkin lymphoma.
- Author
-
Chiu BC, Dave BJ, Ward MH, Fought AJ, Hou L, Jain S, Gapstur S, Evens AM, Zahm SH, Blair A, and Weisenburger DD
- Subjects
- Case-Control Studies, Energy Intake, Female, Humans, In Situ Hybridization, Fluorescence, Lymphoma, Non-Hodgkin epidemiology, Lymphoma, Non-Hodgkin pathology, Male, Nebraska epidemiology, Risk Factors, Chromosomes, Human, Pair 14 genetics, Chromosomes, Human, Pair 18 genetics, Diet, Lymphoma, Non-Hodgkin genetics, Translocation, Genetic genetics
- Abstract
Objective: To evaluate the associations between diet and non-Hodgkin lymphoma (NHL) according to t(14;18) status, one of the most common chromosomal abnormalities in NHL, as t(14;18)-positive NHL represents a genetically more homogeneous group than NHL overall., Methods: We determined the presence of the t(14;18)(q32;q21) by fluorescence in situ hybridization in 172 of 175 tumor blocks from a population-based, case-control study conducted in Nebraska during 1983-1986. Information on the frequency of consumption as an adult of 30 food items was derived from the parent case-control study. Dietary factors in 60 t(14;18)-positive and 87 t(14;18)-negative cases were compared with 1,075 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using polytomous logistic regression., Results: The risk of t(14;18)-positive NHL for the highest versus the lowest approximate tertile of intake was elevated for milk (OR = 2.2; 1.0-5.0) and dietary nitrite (OR = 2.8; 1.3-6.1), whereas coffee consumption was inversely associated with risk (OR = 0.4; 0.2-0.7). We also found inverse associations between the intake of fish (OR = 0.5; 0.3-1.0) and carotene (OR = 0.5; 0.2-0.9) and risk of t(14;18)-negative NHL. There was no association between the intake of meats, vegetables, protein, or vitamin C and risk of either t(14;18)-positive or t(14;18)-negative NHL., Conclusion: We observed differences in associations between diet and t(14;18)-defined subgroups of NHL. These findings should be interpreted cautiously because of the small sample.
- Published
- 2008
- Full Text
- View/download PDF
44. Cytogenetic abnormalities and clinical correlations in peripheral T-cell lymphoma.
- Author
-
Nelson M, Horsman DE, Weisenburger DD, Gascoyne RD, Dave BJ, Loberiza FR, Ludkovski O, Savage KJ, Armitage JO, and Sanger WG
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Female, Follow-Up Studies, Humans, Immunoblastic Lymphadenopathy genetics, Karyotyping, Lymphoma, Large-Cell, Anaplastic genetics, Male, Middle Aged, Prognosis, Survival Analysis, Chromosome Aberrations, Lymphoma, T-Cell, Peripheral genetics
- Abstract
Cytogenetic correlations among most types of peripheral T-cell lymphoma (PTCL) have not been very informative to date. This study aimed to identify recurrent chromosomal abnormalities in angioimmunoblastic T-cell lymphoma (AITL), ALK-negative anaplastic large cell lymphoma (ALK-ALCL) and peripheral T-cell lymphoma, unspecified (PTCL-US), and to evaluate their prognostic value. We reviewed the cytogenetic findings of 90 previously-diagnosed cases of PTCL and correlated the cytogenetic findings with the specific histological subtype. The most common abnormalities for AITL were 5q (55%), 21 (41%) and 3q (36%) gains, concurrent trisomies of 5 and 21 (41%), and loss of 6q (23%). In ALK(-) ALCL, gains of 1q (50%) and 3p (30%), and losses of 16pter (50%), 6q13q21 (30%), 15 (30%), 16qter (30%) and 17p13 (30%) were frequent findings. In PTCL-US, frequent gains involved 7q22q31 (33%), 1q (24%), 3p (20%), 5p (20%), and 8q24qter (22%), and losses of 6q22q24 (26%) and 10p13pter (26%). We did not observe any association between specific chromosomal abnormalities and overall survival (OS). However, cases with complex karyotypes, most frequently observed in ALK(-) ALCL and PTCL-US, had a significantly shorter OS. Although, genetic differences were noted in these subtypes, further studies are needed to determine the key pathogenetic events in PTCL.
- Published
- 2008
- Full Text
- View/download PDF
45. Array-based comparative genomic hybridization analysis of 1176 consecutive clinical genetics investigations.
- Author
-
Pickering DL, Eudy JD, Olney AH, Dave BJ, Golden D, Stevens J, and Sanger WG
- Subjects
- Chromosomes, Artificial, Bacterial genetics, Humans, In Situ Hybridization, Fluorescence, Abnormalities, Multiple genetics, Algorithms, Chromosome Aberrations, Cytogenetics methods, Microarray Analysis methods, Nucleic Acid Hybridization methods
- Abstract
Purpose: Cytogenetic investigations are useful for etiologic determinations of mental retardation, developmental delay, multiple congenital anomalies, and pregnancy complications; however, the causes remain elusive in a majority of cases despite high-resolution cytogenetic studies and multiple fluorescence in situ hybridization examinations. Array-based comparative genomic hybridization has the ability to examine the genome at a higher resolution and may yield an increased detection of genetic abnormalities. The purpose of this study was to assess the use of array-based comparative genomic hybridization in a clinical genetics setting., Methods: DNA from 1176 patients was analyzed using a bacterial artificial chromosome array-based comparative genomic hybridization platform. All abnormal cases were confirmed by fluorescence in situ hybridization and parental studies were completed when possible., Results: Of the 1176 patients included in this survey, 163 showed a genomic imbalance identified by array-based comparative genomic hybridization. Of these 163 cases, 116 had a clinically relevant genetic abnormality. A total of 9.8% (116 of 1176 cases) were determined to exhibit a causative genomic imbalance. Twenty-five of the 116 abnormal cases had a previously identified cytogenetic abnormality yielding an increased detection rate of 7.9% (91 of 1146) in cases with normal or no cytogenetics., Conclusion: Array-based comparative genomic hybridization increases the overall abnormality detection rate, thus improving the diagnostic potential of clinical cytogenetics investigations.
- Published
- 2008
- Full Text
- View/download PDF
46. The utility of t(14;18) in understanding risk factors for non-Hodgkin lymphoma.
- Author
-
Chiu BC, Lan Q, Dave BJ, Blair A, Zahm SH, and Weisenburger DD
- Subjects
- Humans, Risk Factors, Chromosomes, Human, Pair 14 genetics, Chromosomes, Human, Pair 18 genetics, Lymphoma, Non-Hodgkin genetics, Translocation, Genetic
- Abstract
Characteristic chromosomal abnormalities are associated with specific histological subtypes of non-Hodgkin lymphoma (NHL). The chromosomal translocation t(14;18)(q32;q21) is one of the most common chromosomal abnormalities in NHL, occurring in 70%-90% of cases of follicular lymphoma, 20%-30% of diffuse large B-cell lymphoma, and 5%-10% of other less common subtypes. The t(14;18)-positive NHL may represent a homogenous group and, consequently, increase etiologic specificity in epidemiological studies. Although the t(14;18) has important clinical ramifications, its etiologic significance remains to be determined. Two population-based, case-control studies addressed this issue by evaluating potential risk factors for t(14;18)-positive and t(14;18)-negative subgroups of NHL. Both studies found that the association between pesticide exposures and risk of NHL was largely limited to t(14;18)-positive NHL cases. However, the findings regarding cigarette smoking, family history of hematopoietic cancer, and hair dye use were not entirely consistent. These results indicate that defining subgroups of NHL according to t(14;18) status may be useful for etiologic research, particularly for exposures that are genotoxic or may contribute to the development of NHL through pathways involving the t(14;18). Studies to further evaluate these associations and delineate the effects of various exposures in other genetically defined subgroups of NHL are warranted.
- Published
- 2008
- Full Text
- View/download PDF
47. Characterization of a familial small supernumerary marker chromosome in a patient with adult-onset tongue cancer.
- Author
-
Bakshi SR, Dave BJ, Sanger W, Brahmbhatt MM, Trivedi PJ, Kakadia PM, and Patel SJ
- Subjects
- Adult, Child, Chromosome Painting, Cytogenetics, Female, Humans, In Situ Hybridization, Fluorescence, Karyotyping, Male, Middle Aged, Mosaicism, Pedigree, Trisomy, Carcinoma, Squamous Cell genetics, Chromosome Aberrations, Chromosomes, Human, Pair 21 genetics, Tongue Neoplasms genetics
- Abstract
Cytogenetic analysis in peripheral blood lymphocytes of a 50-year-old female with tongue cancer showed the presence of one to three copies of a small supernumerary marker chromosome (sSMC) in a mosaic state. Family studies also revealed the marker in mosaic form in four (age <29 years) of eleven clinically normal individuals studied from her family of 16 individuals spanning three generations. Due to the extremely small size of the marker chromosome, identification by classical cytogenetics was not informative. Multicolor FISH followed by whole chromosome painting identified the marker as a derivative of chromosome 21. This is the first report of sSMC21 in an adult-onset tongue cancer patient and some of her family members with no clinical symptoms., ((c) 2008 S. Karger AG, Basel.)
- Published
- 2008
- Full Text
- View/download PDF
48. Mutations in the DNA-binding codons of TP53, which are associated with decreased expression of TRAILreceptor-2, predict for poor survival in diffuse large B-cell lymphoma.
- Author
-
Young KH, Weisenburger DD, Dave BJ, Smith L, Sanger W, Iqbal J, Campo E, Delabie J, Gascoyne RD, Ott G, Rimsza L, Müller-Hermelink HK, Jaffe ES, Rosenwald A, Staudt LM, Chan WC, and Greiner TC
- Subjects
- Binding Sites, Codon, Gene Expression Regulation, Neoplastic, Humans, Lymphoma, Large B-Cell, Diffuse mortality, Prognosis, Lymphoma, Large B-Cell, Diffuse genetics, Mutation, Receptors, TNF-Related Apoptosis-Inducing Ligand genetics, Tumor Suppressor Protein p53 genetics
- Abstract
Mutations of the TP53 tumor suppressor gene have been associated with poor survival in some series of diffuse large B-cell lymphoma (DLBCL) but not in other studies. The purpose of this study was to identify the frequency of TP53 alterations (mutations or deletions), characterize the gene expression of mutant/deleted cases, and determine the effects of mutations on survival. In a series of DLBCL that had previous gene expression profiling, we identified 24 mutations in 113 cases (21%). There was no difference in the frequency of mutations in the molecular subgroups of DLBCL. Twelve (50%) of the 24 cases had mutations localized to the DNA-binding codons in the core domain of TP53. The presence of any TP53 mutation correlated with poor overall survival (OS; P = .044), but DNA-binding mutations were the most significant predictor of poor OS (P < .001). Multivariate analysis confirmed that the International Prognostic Index, tumor size, and TP53 DNA-binding mutations were independent predictors of OS. Gene expression analysis showed that TRAILreceptor-2 (DR5) was the most differentially underexpressed gene in the TP53 mutated cases. Investigation is warranted into targeted therapy toward TRAIL receptor-2, to potentially bypass the adverse effect of mutated TP53 in DLBCL.
- Published
- 2007
- Full Text
- View/download PDF
49. Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma.
- Author
-
Iqbal J, Greiner TC, Patel K, Dave BJ, Smith L, Ji J, Wright G, Sanger WG, Pickering DL, Jain S, Horsman DE, Shen Y, Fu K, Weisenburger DD, Hans CP, Campo E, Gascoyne RD, Rosenwald A, Jaffe ES, Delabie J, Rimsza L, Ott G, Müller-Hermelink HK, Connors JM, Vose JM, McKeithan T, Staudt LM, and Chan WC
- Subjects
- DNA Mutational Analysis, Exons, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, In Situ Hybridization, Fluorescence, Introns, Lymphoma, Large B-Cell, Diffuse metabolism, Models, Genetic, Prognosis, Proto-Oncogene Proteins c-bcl-6, RNA, Messenger metabolism, Time Factors, Translocation, Genetic, Treatment Outcome, DNA-Binding Proteins biosynthesis, Lymphoma, Large B-Cell, Diffuse genetics, Mutation
- Abstract
Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed biologically and prognostically distinct subgroups: germinal center B-cell-like (GCB), activated B-cell-like (ABC) and primary mediastinal (PM) DLBCL. The BCL6 gene is often translocated and/or mutated in DLBCL. Therefore, we examined the BCL6 molecular alterations in these DLBCL subgroups, and their impact on BCL6 expression and BCL6 target gene repression. BCL6 translocations at the major breakpoint region (MBR) were detected in 25 (18.8%) of 133 DLBCL cases, with a higher frequency in the PM (33%) and ABC (24%) subgroups than in the GCB (10%) subgroup. Translocations at the alternative breakpoint region (ABR) were detected in five (6.4%) of 78 DLBCL cases, with three cases in ABC and one case each in the GCB and the unclassifiable subgroups. The translocated cases involved IgH and non-IgH partners in about equal frequency and were not associated with different levels of BCL6 mRNA and protein expression. BCL6 mutations were detected in 61% of DLBCL cases, with a significantly higher frequency in the GCB and PM subgroups (>70%) than in the ABC subgroup (44%). Exon-1 mutations were mostly observed in the GCB subgroup. The repression of known BCL6 target genes correlated with the level of BCL6 mRNA and protein expression in GCB and ABC subgroups but not with BCL6 translocation and intronic mutations. No clear inverse correlation between BCL6 expression and p53 expression was observed. Patients with higher BCL6 mRNA or protein expression had a significantly better overall survival. The biological role of BCL6 in translocated cases where repression of known target genes is not demonstrated is intriguing and warrants further investigation.
- Published
- 2007
- Full Text
- View/download PDF
50. Molecular basis of aggressive disease in chronic lymphocytic leukemia patients with 11q deletion and trisomy 12 chromosomal abnormalities.
- Author
-
Mittal AK, Hegde GV, Aoun P, Bociek RG, Dave BJ, Joshi AD, Sanger WG, Weisenburger DD, and Joshi SS
- Subjects
- Activating Transcription Factors metabolism, Cluster Analysis, Cytogenetic Analysis, Disease Progression, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genes, Neoplasm, Humans, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Male, Middle Aged, Prognosis, Time Factors, Treatment Outcome, Chromosome Deletion, Chromosomes, Human, Pair 11 genetics, Chromosomes, Human, Pair 12 genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Trisomy genetics
- Abstract
In B-cell chronic lymphocytic leukemia (CLL), Rai stage, immunoglobulin gene mutational status, chromosomal abnormalities, CD38 and ZAP-70 expression were used as prognostic markers. In this study, to understand the molecular basis of chromosomal abnormalities leading to tumor progression, 90 CLL patients were grouped into poor prognosis (with 11q deletion and trisomy 12) and good prognosis (with normal karyotype and 13q deletion) and their clinical outcome was assessed. Gene expression profiles of 35 CLL samples with poor outcome (11q deletion, n=9; trisomy 12, n=5) and good outcome (13q deletion, n=13; normal karyotype, n=8) were analyzed using oligonucleotide microarray. Significance analysis of microarray (SAM) identified 27 differentially expressed genes between these two subgroups with significant overexpression of ATF5 and underexpression of CDC16, PCDH8, SLAM, MNDA and ATF2 in CLL patients with poor outcome. ATF5 gene expression in CLL was further studied because of its role in the regulation of cell cycle progression/differentiation and apoptosis. The overexpression of ATF5 was confirmed by real-time PCR using 39 CLL samples from the poor and good outcome groups. ATF5 was significantly (p<0.001) overexpressed in the poor outcome group. Furthermore, ATF5 expression was significantly higher in the 11q deletion as well as trisomy 12 group alone compared to the 13q deletion and normal karyotype groups. ATF5 overexpression was also associated with significantly (p=0.04) shorter time to treatment. Similarly, expression of five underexpressed genes also correlated with longer time to treatment. Thus, this report demonstrates that ATF5 may be one of the key genes involved in increased proliferation and survival in 11q deletion or trisomy 12, whereas CD16, CD86, SLAM, MNDA and ATF2 may be involved in the decreased proliferation of CLL cells with 13q deletion or normal karyotype.
- Published
- 2007
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.