Chromosome translocations in multiple myeloma.
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TLDR
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.read more
Citations
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A molecular compendium of genes expressed in multiple myeloma.
Jaime O. Claudio,Esther Masih-Khan,Esther Masih-Khan,Hongchang Tang,Hongchang Tang,Jason Goncalves,Jason Goncalves,Michael Voralia,Michael Voralia,Zhi Hua Li,Zhi Hua Li,Vincent Nadeem,Vincent Nadeem,Eva Cukerman,Eva Cukerman,Ofelia Francisco-Pabalan,Ofelia Francisco-Pabalan,Choong Chin Liew,Choong Chin Liew,James R. Woodgett,James R. Woodgett,A. Keith Stewart +21 more
TL;DR: A molecular resource of genes expressed in primary malignant plasma cells using a combination of cDNA library construction, 5' end single-pass sequencing, bioinformatics, and microarray analysis, which contains numerous genes of unknown function and may complement other commercially available arrays in defining the molecular portrait of this hematopoietic malignancy.
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Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma.
Maurizio Affer,Marta Chesi,W D Chen,Jonathan J Keats,Yulia N. Demchenko,K Tamizhmani,Victoria M. Garbitt,Daniel L. Riggs,Leslie A. Brents,A V Roschke,S Van Wier,R Fonseca,P L Bergsagel,W. M. Kuehl +13 more
TL;DR: It appears that increased MYC expression at the MGUS/MM transition usually is biallelic, but sometimes can be monoallelic if there is an MYC rearrangement.
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A practical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy
Alexander Keith Stewart,P L Bergsagel,P R Greipp,Angela Dispenzieri,Morie A. Gertz,Suzanne R. Hayman,Shaji Kumar,Martha Q. Lacy,John A. Lust,Stephen J. Russell,T. E. Witzig,Steven R. Zeldenrust,David Dingli,Craig B. Reeder,Vivek Roy,Robert A. Kyle,S V Rajkumar,R Fonseca +17 more
TL;DR: A consensus high-risk definition is provided and practical guidelines for the adoption of routine diagnostic testing are offered and it is proposed that this classification will identify most of the 25% of MM patients for whom current therapies are inadequate and for whom investigational regimens should be vigorously pursued.
References
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Book
Cancer : Principles and Practice of Oncology
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Journal ArticleDOI
Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells
Riccardo Dalla-Favera,Marco Bregni,Jan Erikson,David A. Patterson,Robert C. Gallo,Carlo M. Croce +5 more
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.
Journal ArticleDOI
Cellular Origin of Human B-Cell Lymphomas
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Journal ArticleDOI
The Proto-Oncogene c-maf Is Responsible for Tissue-Specific Expression of Interleukin-4
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.
Journal ArticleDOI
Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3.
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.
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