Chromosome translocations in multiple myeloma.
TL;DR: Oncogenes dysregulated by primary IgH translocations in MM do not appear to confer an anti-apoptotic effect, but instead increase proliferation and/or inhibit differentiation.
Abstract: Multiple myeloma (MM), a malignant tumor of somatically mutated, isotype-switched plasma cells (PC), usually arises from a common benign PC tumor called Monoclonal Gammopathy of Undetermined Significance (MGUS). MM progresses within the bone marrow, and then to an extramedullary stage from which MM cell lines are generated. The incidence of IgH translocations increases with the stage of disease: 50% in MGUS, 60–65% in intramedullarly MM, 70–80% in extramedullary MM, and >90% in MM cell lines. Primary, simple reciprocal IgH translocations, which are present in both MGUS and MM, involve many partners and provide an early immortalizing event. Four chromosomal partners appear to account for the majority of primary IgH translocations: 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (FGFR3 and MMSET), and 16q23 (c-maf). They are mediated primarily by errors in IgH switch recombination and less often by errors in somatic hypermutation, with the former dissociating the intronic and 3′ enhancer(s), so that potential oncogenes can be dysregulated on each derivative chromosome (e.g., FGFR3 on der14 and MMSET on der4). Secondary translocations, which sometimes do not involve Ig loci, are more complex, and are not mediated by errors in B cell specific DNA modification mechanisms. They involve other chromosomal partners, notably 8q24 (c-myc), and are associated with tumor progression. Consistent with MM being the malignant counterpart of a long-lived PC, oncogenes dysregulated by primary IgH translocations in MM do not appear to confer an anti-apoptotic effect, but instead increase proliferation and/or inhibit differentiation. The fact that so many different primary transforming events give rise to tumors with the same phenotype suggests that there is only a single fate available for the transformed cell.
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29 Sep 2017
TL;DR: Thank you very much for reading who classification of tumours of haematopoietic and lymphoid tissues, and maybe you have knowledge that, people have look hundreds of times for their chosen readings like this, but end up in malicious downloads.
Abstract: WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES , WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES , کتابخانه مرکزی دانشگاه علوم پزشکی تهران
13,835 citations
TL;DR: Recent oncogenomic studies have further advanced the understanding of the molecular pathogenesis of multiple myeloma, providing the framework for new prognostic classification and identifying new therapeutic targets.
Abstract: Multiple myeloma is a plasma cell malignancy characterized by complex heterogeneous cytogenetic abnormalities. The bone marrow microenvironment promotes multiple myeloma cell growth and resistance to conventional therapies. Although multiple myeloma remains incurable, novel targeted agents, used alone or in combination, have shown great promise to overcome conventional drug resistance and improve patient outcome. Recent oncogenomic studies have further advanced our understanding of the molecular pathogenesis of multiple myeloma, providing the framework for new prognostic classification and identifying new therapeutic targets.
875 citations
TL;DR: Multiple myeloma is a neoplasm of terminally differentiated B cells (plasma cells) in which chromosome translocations frequently place oncogenes under the control of immunoglobulin enhancers.
Abstract: Multiple myeloma is a neoplasm of terminally differentiated B cells (plasma cells) in which chromosome translocations frequently place oncogenes under the control of immunoglobulin enhancers. Unlike most haematopoietic cancers, multiple myeloma often has complex chromosomal abnormalities that are reminiscent of epithelial tumours. What causes full-blown myeloma? And can our molecular understanding of this common haematological malignancy be used to develop effective preventive and treatment strategies?
799 citations
TL;DR: The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment.
Abstract: Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment.
746 citations
TL;DR: This summary describes the consensus recommendations arising from that meeting with special emphasis on novel genetic observations and Gene expression platforms capable of detecting many of the genetic aberrations found in the clonal cells of myeloma.
Abstract: Much has been learned regarding the biology and clinical implications of genetic abnormalities in multiple myeloma. Because of recent advances in the field, an International Workshop was held in Paris in february of 2003. This summary describes the consensus recommendations arising from that meeting with special emphasis on novel genetic observations. For instance, it is increasingly clear that translocations involving the immunoglobin heavy-chain locus are important for the pathogenesis of one-half of patients. As a corollary, it also clear that the remaining patients, lacking IgH translocations, have hyperdiploidy as the hallmark of their disease. Several important genetic markers are associated with a shortened survival such as chromosome 13 monosomy, hypodiploidy, and others. The events leading the transformation of the monoclonal gammopathy of undetermined significance (MGUS) to myeloma are still unclear. One of the few differential genetic lesions between myeloma and MGUS is the presence of ras mutations in the latter. Gene expression platforms are capable of detecting many of the genetic aberrations found in the clonal cells of myeloma. Areas in need of further study were identified. The study of the genetic aberrations will likely form the platform for targeted therapy for the disease.
686 citations
Cites background from "Chromosome translocations in multip..."
...Although most IgH translocations in MM occur at the time of isotype switching, the t(11;14)(q13;q32) may involve nonswitch IgH loci and could be mediated via other B-cell-specific mechanisms such as somatic hypermutation, and may even be a secondary translocation in some cases (9)....
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...Variant c-maf translocations also include the IgL- locus in the human MM cell line 8226 (9, 40)....
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...The biology associated with these abnormalities and reported recurrent prevalence favors their participation in the process of disease pathogenesis (8, 9)....
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References
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01 Jan 1982
TL;DR: Part I: Molecular Biology of Cancer Molecular Methods in Oncology Section 1. Amplification Techniques Section 2. RNA Interference Section 3. cDNA arrays Section 4. Tissue arrays Section 5. Cytogenetics Section 6. Bioinformatics Genomics and Proteomics Molecular Targets in oncology.
Abstract: Part I: Molecular Biology of Cancer Molecular Methods in Oncology Section 1. Amplification Techniques Section 2. RNA Interference Section 3. cDNA arrays Section 4. Tissue arrays Section 5. Cytogenetics Section 6. Bioinformatics Genomics and Proteomics Molecular Targets in Oncology Section 1. Signal transduction systems Section 2. Cell cycle Section 3. Apoptosis Section 4. Telomerase Invasion and Metastases Angiogenesis Cancer Immunology Part II: Principles of Oncology Etiology of Cancer: Viruses Section 1. RNA Viruses Section 2. DNA Viruses Etiology of Cancer: Chemical Factors Etiology of Cancer: Tobacco Etiology of Cancer: Physical Factors Epidemiology of Cancer Section 1. Epidemiologic Methods Section 2. Cancer Statistics Principles of Surgical Oncology Section 1. General Issues Section 2. Laparascopic Surgery Principles of Radiation Oncology Principles of Medical Oncology Pharmacology of Cancer Chemotherapy Section 2. Pharmocokinetics Section 3. Pharmacogenomics Section 4. Alkylating Agents Section 5. Cisplatin and its Analogues Section 6. Antimetabolites Section 7. Topoisomerase Interactive Agents Section 8. Antimicrotubule Agents Section 9. Miscellaneous Chemotherapeutic Agents Pharmacology of Cancer Biotherapeutics Section 1. Interferon Section 2. Interleukin 2 Section 3. Histone deacetylase inhibitors as differentiation agents Section 4. Monoclonal Antibodies Pharmacology of Endocrine Manipulation Design and Analysis of Clinical Trials Part III: Practice of Oncology Cancer Prevention: Preventing Tobacco-Related Cancers Cancer Prevention: Diet and Chemopreventive Agents Section 1. Dietary fat Section 2. Dietary Fiber Section 3. Dietary fruits and vegetables: naturally occurring anticarcinogens Section 4. Retinoids, carotenoids and micronutrients Section 5. Dietary Carcinogens Section 6. Cyclo-oxygenase inhibitors Section 7. Physical Activity and Body Weight Cancer Prevention: Role of Surgery in Cancer Prevention Cancer Screening Advanced Molecular Diagnostics Advanced Imaging Methods Section 1. Functional and Metabolic Imaging Section 2. Interventional Radiology Cancer Diagnosis: Endoscopy Section 1. Gastrointestinal endoscopy Section 2. Respiratory Tract Cancer of the Head and Neck Section 1. Molecular Biology of Head and Neck Tumors Section 2. Treatment of Head and Neck Cancers Section 3. Rehabilitation after Treatment for Head Cancer of the Lung Section 1. Molecular Biology of Lung Cancer Section 2. Non-small Cell Lung Cancer Section 3. Small Cell Lung Cancer Neoplasms of the Mediastinum Cancers of the Gastrointestinal Tract
9,166 citations
TL;DR: Using a DNA probe that is specific for the complete gene (c-myc), different somatic cell hybrids possessing varying numbers of human chromosomes were analyzed by the Southern blotting technique and results indicate that the human c- myc gene is located on chromosome 8.
Abstract: Human sequences related to the transforming gene (v-myc) of avian myelocytomatosis virus (MC29) are represented by at least one gene and several related sequences that may represent pseudogenes. By using a DNA probe that is specific for the complete gene (c-myc), different somatic cell hybrids possessing varying numbers of human chromosomes were analyzed by the Southern blotting technique. The results indicate that the human c-myc gene is located on chromosome 8. The analysis of hybrids between rodent cells and human Burkitt lymphoma cells, which carry a reciprocal translocation between chromosomes 8 and 14, allowed the mapping of the human c-myc gene on region (q24 leads to qter) of chromosome 8. This chromosomal region is translocated to either human chromosome 2, 14, or 22 in Burkitt lymphoma cells.
1,632 citations
"Chromosome translocations in multip..." refers background in this paper
...…translocations in MM Chromosomal translocations that dysregulate c-myc by juxtaposing it with one of the three Ig loci represent an essentially invariant and apparently primary event in human Burkitt's lymphoma and murine plasmacytoma tumors (Dalla-Favera et al., 1982; Shen-Ong et al., 1982)....
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TL;DR: The origin of human lymphomas has been studied by various approaches, including histology and immunophenotyping, but sequence analysis of the variable-region genes of B-cell lymphomas offered a molecular approach to studying the origin of the tumors.
Abstract: The origin of human lymphomas has been studied by various approaches, including histology and immunophenotyping. In some types of lymphoma these studies suggested the cellular origin, but in many instances the origin could not be identified. When somatic mutations of the genes for the variable region of the B-lymphocyte antigen receptor proved to be a hallmark of germinal-center B cells and their descendants, sequence analysis of the variable-region genes of B-cell lymphomas offered a molecular approach to studying the origin of the tumors. Before discussing the results of these studies, we outline the human peripheral B-cell repertoire and its generation. . . .
709 citations
"Chromosome translocations in multip..." refers background in this paper
...Errors in any of these three B cell speci®c DNA modi®cations, each of which can `spill over' to a ect non-Ig genes, can result in chromosomal translocations, deletions, insertions, and even point mutations (Kuppers et al., 1999)....
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TL;DR: The proto-oncogene c-maf, a basic region/leucine zipper transcription factor, controls tissue-specific expression of IL-4 in Th1 cells, B cells, and nonlymphoid cells and acts in synergy with the nuclear factor of activated T cells (NF-ATp) to initiate endogeneous IL- 4 production by B cells.
689 citations
"Chromosome translocations in multip..." refers background in this paper
...In lymphoid cells it has been characterized as a T cell transcription factor expressed speci®cally in TH2 lymphocytes that controls the expression of IL-4 (Ho et al., 1996)....
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TL;DR: It is proposed that after the t(4;14) translocation, somatic mutation during tumour progression frequently generates an FGFR3 protein that is active in the absence of ligand.
Abstract: Dysregulation of oncogenes by translocation to the IgH locus (14q32) is a seminal event in the pathogenesis of B-cell tumours In multiple myeloma (MM), translocations to the IgH locus have been reported at an incidence of 20-60% For most translocations, the partner chromosome is unknown (14q+); for the others, a diverse array of chromosomal partners have been identified, with 11q13 (cyclin D1) the only chromosome that is frequently involved Recently, we developed a Southern-blot assay that detects translocation breakpoint fragments in most MM tumours, including those with no translocation detected by conventional karyotyping In a continuing analysis of translocation in 21 myeloma cell lines and primary tumours, we show that the novel, karyotypically silent translocation t(4;14)(p163;q323) is present in five lines and at least three of ten primary tumours The chromosome-4 breakpoints are clustered in a 70-kb region centromeric to the fibroblast growth factor receptor 3 gene (FGFR3), the apparent dysregulated oncogene Two lines and one primary tumour with this translocation selectively express an FGFR3 allele containing activating mutations identified previously in thanatophoric dwarfism We propose that after the t(4;14) translocation, somatic mutation during tumour progression frequently generates in FGFR3 protein that is active in the absence of ligand
676 citations
"Chromosome translocations in multip..." refers background in this paper
...…of conventional cytogenetics, SKY analyses, metaphase FISH analyses, isolation of molecular clones, and RT±PCR assays (Bergsagel et al., 1996; Chesi et al., 1997, 1998a; Gabrea et al., 1999; Shaughnessy et al., 2001; Shou et al., 2000; Kuehl, 2001, unpublished results), we have identi®ed at…...
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...…and others have cloned 40 IgH translocation breakpoints (but no IgL translocation breakpoints) in MM cell lines and tumors (Bergsagel et al., 1996; Chesi et al., 1996, 1997, 1998a; Gabrea et al., 1999; Hatzivassiliou et al., 2001; Iida et al., 1997; Pratt et al., 2001; Richelda et al., 1997;…...
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