{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T07:18:44Z","timestamp":1790320724243,"version":"4.1.0"},"reference-count":42,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2005,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Multiple myeloma is a tumor of somatically mutated, isotype-switched plasma cells that accumulate in the bone marrow leading to bone destruction and bone marrow failure. The germinal center processes of somatic hypermutation and switch recombination are implicated in the development of recurrent immunoglobulin gene translocations in 40% of patients. These affect five loci: 11q13, 6p21, 4p16, 16q23 and 20q11, leading to dysregulation of CCND1, CCND2, FGFR3\/MMSET, c-MAF and MAFB respectively. The remaining 60% of patients can be divided into four groups based on their expression of CCND1 and CCND2. The largest group (40%) ectopically express CCND1 bi-allelically and have hyperdiploidy with multiple trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19 and 21. The translocation and cyclin D (TC) groups identify patients with different genetics, biology, clinical features, prognosis and response to therapy.<\/jats:p>","DOI":"10.1182\/asheducation-2005.1.346","type":"journal-article","created":{"date-parts":[[2005,11,23]],"date-time":"2005-11-23T01:29:34Z","timestamp":1132709374000},"page":"346-352","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":60,"title":["Early Genetic Events Provide the Basis for a Clinical Classification of Multiple Myeloma"],"prefix":"10.1182","volume":"2005","author":[{"given":"W. Michael","family":"Kuehl","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. Leif","family":"Bergsagel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2019111701362179000_R1","unstructured":"Ries LAG, Eisner MP, Kosary CL, et al. SEER Cancer Statistics Review, 1975\u20132001. Bethesda: National Cancer Institute; 2004."},{"key":"2019111701362179000_R2","unstructured":"Malpas JS, Bergsagel DE, Kyle R, Anderson K. Myeloma: Biology and Management (ed 3rd). Oxford: Elsevier; 2004."},{"key":"2019111701362179000_R3","doi-asserted-by":"crossref","unstructured":"Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346:564\u2013569.","DOI":"10.1056\/NEJMoa01133202"},{"key":"2019111701362179000_R4","doi-asserted-by":"crossref","unstructured":"Lynch HT, Watson P, Tarantolo S, et al. Phenotypic heterogeneity in multiple myeloma families. J Clin Oncol. 2005;23:685\u2013693.","DOI":"10.1200\/JCO.2005.10.126"},{"key":"2019111701362179000_R5","doi-asserted-by":"crossref","unstructured":"Kuppers R, Klein U, Hansmann ML, Rajewsky K. Cellular origin of human B-cell lymphomas. N Engl J Med. 1999;341:1520\u20131529.","DOI":"10.1056\/NEJM199911113412007"},{"key":"2019111701362179000_R6","doi-asserted-by":"crossref","unstructured":"Shapiro-Shelef M, Calame K. Regulation of plasma-cell development. Nat Rev Immunol. 2005;5:230\u2013242.","DOI":"10.1038\/nri1572"},{"key":"2019111701362179000_R7","doi-asserted-by":"crossref","unstructured":"Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer. 2002;2:175\u2013187.","DOI":"10.1038\/nrc746"},{"key":"2019111701362179000_R8","doi-asserted-by":"crossref","unstructured":"Stevenson FK, Sahota SS, Ottensmeier CH, Zhu D, Forconi F, Hamblin TJ. The occurrence and significance of V gene mutations in B cell-derived human malignancy. Adv Cancer Res. 2001;83:81\u2013116.","DOI":"10.1016\/S0065-230X(01)83004-9"},{"key":"2019111701362179000_R9","doi-asserted-by":"crossref","unstructured":"Zojer N, Ludwig H, Fiegl M, Stevenson FK, Sahota SS. Patterns of somatic mutations in VH genes reveal pathways of clonal transformation from MGUS to multiple myeloma. Blood. 2003;101:4137\u20134139.","DOI":"10.1182\/blood-2002-09-2825"},{"key":"2019111701362179000_R10","doi-asserted-by":"crossref","unstructured":"Matsui W, Huff CA, Wang Q, et al. Characterization of clonogenic multiple myeloma cells. Blood. 2004;103:2332\u20132336.","DOI":"10.1182\/blood-2003-09-3064"},{"key":"2019111701362179000_R11","doi-asserted-by":"crossref","unstructured":"Yata K, Yaccoby S. The SCID-rab model: a novel in vivo system for primary human myeloma demonstrating growth of CD138-expressing malignant cells. Leukemia. 2004;18:1891\u20131897.","DOI":"10.1038\/sj.leu.2403513"},{"key":"2019111701362179000_R12","unstructured":"Bradwell AR, Mead GP, Carr-Smith HD. Serum Free Light Chain Analysis (ed 3rd). Birmingham: The Binding Site Ltd.; 2005."},{"key":"2019111701362179000_R13","doi-asserted-by":"crossref","unstructured":"Kuppers R, Dalla-Favera R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene. 2001;20:5580\u20135594.","DOI":"10.1038\/sj.onc.1204640"},{"key":"2019111701362179000_R14","doi-asserted-by":"crossref","unstructured":"Bergsagel PL, Kuehl WM. Chromosomal translocations in multiple myeloma. Oncogene. 2001;20:5611\u20135622.","DOI":"10.1038\/sj.onc.1204641"},{"key":"2019111701362179000_R15","doi-asserted-by":"crossref","unstructured":"Fonseca R, Bailey RJ, Ahmann GJ, et al. Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood. 2002;100:1417\u20131424.","DOI":"10.1182\/blood.V100.4.1417.h81602001417_1417_1424"},{"key":"2019111701362179000_R16","doi-asserted-by":"crossref","unstructured":"Fonseca R, Blood E, Rue M, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood. 2003;101:4569\u20134575.","DOI":"10.1182\/blood-2002-10-3017"},{"key":"2019111701362179000_R17","doi-asserted-by":"crossref","unstructured":"Avet-Loiseau H, Facon T, Grosbois B, et al. Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation. Blood. 2002;99:2185\u20132191.","DOI":"10.1182\/blood.V99.6.2185"},{"key":"2019111701362179000_R18","doi-asserted-by":"crossref","unstructured":"Avet-Loiseau H, Garand R, Lode L, Harousseau JL, Bataille R. Translocation t(11;14)(q13;q32) is the hallmark of IgM, IgE, and nonsecretory multiple myeloma variants. Blood. 2003;101:1570\u20131571.","DOI":"10.1182\/blood-2002-08-2436"},{"key":"2019111701362179000_R19","doi-asserted-by":"crossref","unstructured":"Hayman SR, Bailey RJ, Jalal SM, et al. Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis. Blood. 2001;98:2266\u20132268.","DOI":"10.1182\/blood.V98.7.2266"},{"key":"2019111701362179000_R20","doi-asserted-by":"crossref","unstructured":"Avet-Loiseau H, Gerson F, Margrangeas F, Minvielle S, Harousseau J-L, Bataille R. Rearrangements of the c-myc oncogene are present in 15% of primary human multiple myeloma tumors. Blood. 2001;98:3082\u20133086.","DOI":"10.1182\/blood.V98.10.3082"},{"key":"2019111701362179000_R21","doi-asserted-by":"crossref","unstructured":"Shou Y, Martelli ML, Gabrea A, et al. Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma. Proc Natl Acad Sci U S A. 2000;97:228\u2013233.","DOI":"10.1073\/pnas.97.1.228"},{"key":"2019111701362179000_R22","doi-asserted-by":"crossref","unstructured":"Fonseca R, Barlogie B, Bataille R, et al. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res. 2004;64:1546\u20131558.","DOI":"10.1158\/0008-5472.CAN-03-2876"},{"key":"2019111701362179000_R23","doi-asserted-by":"crossref","unstructured":"Kaufmann H, Ackermann J, Baldia C, et al. Both IGH translocations and chromosome 13q deletions are early events in monoclonal gammopathy of undetermined significance and do not evolve during transition to multiple myeloma. Leukemia. 2004;18:1879\u20131882.","DOI":"10.1038\/sj.leu.2403518"},{"key":"2019111701362179000_R24","doi-asserted-by":"crossref","unstructured":"Sawyer JR, Lukacs JL, Thomas EL, et al. Multicolour spectral karyotyping identifies new translocations and a recurring pathway for chromosome loss in multiple myeloma. Brit J Haematol. 2001;112:167\u2013174.","DOI":"10.1046\/j.1365-2141.2001.02546.x"},{"key":"2019111701362179000_R25","doi-asserted-by":"crossref","unstructured":"Smadja NV, Bastard C, Brigaudeau C, Leroux D, Fruchart C. Hypodiploidy is a major prognostic factor in multiple myeloma. Blood. 2001;98:2229\u20132238.","DOI":"10.1182\/blood.V98.7.2229"},{"key":"2019111701362179000_R26","doi-asserted-by":"crossref","unstructured":"Smadja NV, Leroux D, Soulier J, et al. Further cytogenetic characterization of multiple myeloma confirms that 14q32 translocations are a very rare event in hyperdiploid cases. Genes Chromosomes Cancer. 2003;38:234\u2013239.","DOI":"10.1002\/gcc.10275"},{"key":"2019111701362179000_R27","doi-asserted-by":"crossref","unstructured":"Fonseca R, Debes-Marun CS, Picken EB, et al. The recurrent IgH translocations are highly associated with non-hyperdiploid variant multiple myeloma. Blood. 2003;102:2562\u20132567.","DOI":"10.1182\/blood-2003-02-0493"},{"key":"2019111701362179000_R28","doi-asserted-by":"crossref","unstructured":"Fassas AB, Spencer T, Sawyer J, et al. Both hypodiploidy and deletion of chromosome 13 independently confer poor prognosis in multiple myeloma. Br J Haematol. 2002;118:1041\u20131047.","DOI":"10.1046\/j.1365-2141.2002.03757.x"},{"key":"2019111701362179000_R29","doi-asserted-by":"crossref","unstructured":"Bergsagel PL, Kuehl WM, Zhan F, Sawyer J, Barlogie B, Shaughnessy J. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood. 2005;Epub ahead of print.","DOI":"10.1182\/blood-2005-01-0034"},{"key":"2019111701362179000_R30","doi-asserted-by":"crossref","unstructured":"Takahashi T, Shivapurkar N, Reddy J, et al. DNA methylation profiles of lymphoid and hematopoietic malignancies. Clin Cancer Res. 2004;10:2928\u20132935.","DOI":"10.1158\/1078-0432.CCR-03-0716"},{"key":"2019111701362179000_R31","unstructured":"Fonseca R, Harrington D, Oken MM, et al. Biological and prognostic significance of interphase fluorescence in situ hybridization detection of chromosome 13 abnormalities (delta13) in multiple myeloma: an eastern cooperative oncology group study. Cancer Res. 2002;62:715\u2013720."},{"key":"2019111701362179000_R32","doi-asserted-by":"crossref","unstructured":"Moreau P, Facon T, Leleu X, et al. Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy. Blood. 2002;100:1579\u20131583.","DOI":"10.1182\/blood-2002-03-0749"},{"key":"2019111701362179000_R33","doi-asserted-by":"crossref","unstructured":"Gertz MA, Lacy MQ, Dispenzieri A, et al. Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy. Blood. 2005.","DOI":"10.1182\/blood-2005-04-1411"},{"key":"2019111701362179000_R34","doi-asserted-by":"crossref","unstructured":"Fonseca R, Blood EA, Oken MM, et al. Myeloma and the t(11;14)(q13;q32); evidence for a biologically defined unique subset of patients. Blood. 2002;99:3735\u20133741.","DOI":"10.1182\/blood.V99.10.3735"},{"key":"2019111701362179000_R35","doi-asserted-by":"crossref","unstructured":"Garand R, Avet-Loiseau H, Accard F, Moreau P, Harousseau JL, Bataille R. t(11;14) and t(4;14) translocations correlated with mature lymphoplasmacytoid and immature morphology, respectively, in multiple myeloma. Leukemia. 2003;17:2032\u20132035.","DOI":"10.1038\/sj.leu.2403091"},{"key":"2019111701362179000_R36","doi-asserted-by":"crossref","unstructured":"Debes-Marun CS, Dewald GW, Bryant S, et al. Chromosome abnormalities clustering and its implications for pathogenesis and prognosis in myeloma. Leukemia. 2003;17:427\u2013436.","DOI":"10.1038\/sj.leu.2402797"},{"key":"2019111701362179000_R37","doi-asserted-by":"crossref","unstructured":"Konigsberg R, Zojer N, Ackermann J, et al. Predictive role of interphase cytogenetics for survival of patients with multiple myeloma. J Clin Oncol. 2000;18:804\u2013812.","DOI":"10.1200\/JCO.2000.18.4.804"},{"key":"2019111701362179000_R38","doi-asserted-by":"crossref","unstructured":"Shaughnessy J, Jacobson J, Sawyer J, et al. Continuous absence of metaphase-defined cytogenetic abnormalities, especially of chromosome 13 and hypodiploidy, ensures long-term survival in multiple myeloma treated with Total Therapy I: interpretation in the context of global gene expression. Blood. 2003;101:3849\u20133856.","DOI":"10.1182\/blood-2002-09-2873"},{"key":"2019111701362179000_R39","doi-asserted-by":"crossref","unstructured":"Shaughnessy J, Jr., Tian E, Sawyer J, et al. Prognostic impact of cytogenetic and interphase fluorescence in situ hybridization-defined chromosome 13 deletion in multiple myeloma: early results of total therapy II. Br J Haematol. 2003;120:44\u201352.","DOI":"10.1046\/j.1365-2141.2003.03948.x"},{"key":"2019111701362179000_R40","doi-asserted-by":"crossref","unstructured":"Trudel S, Ely SA, Farooqi Y, et al. Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma. Blood. 2004;103:3521\u20133528.","DOI":"10.1182\/blood-2003-10-3650"},{"key":"2019111701362179000_R41","doi-asserted-by":"crossref","unstructured":"Barlogie B, Shaughnessy J, Tricot G, et al. Treatment of multiple myeloma. Blood. 2004;103:20\u201332.","DOI":"10.1182\/blood-2003-04-1045"},{"key":"2019111701362179000_R42","doi-asserted-by":"crossref","unstructured":"Hideshima T, Anderson KC. Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev Cancer. 2002;2:927\u2013937.","DOI":"10.1038\/nrc952"}],"container-title":["Hematology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/hematology\/article-pdf\/2005\/1\/346\/645095\/346.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/hematology\/article-pdf\/2005\/1\/346\/645095\/346.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,11,17]],"date-time":"2019-11-17T06:36:40Z","timestamp":1573972600000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/hematology\/article\/2005\/1\/346\/19271\/Early-Genetic-Events-Provide-the-Basis-for-a"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,1,1]]},"references-count":42,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2005,1,1]]}},"URL":"https:\/\/doi.org\/10.1182\/asheducation-2005.1.346","relation":{},"ISSN":["1520-4391","1520-4383"],"issn-type":[{"value":"1520-4391","type":"print"},{"value":"1520-4383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,1,1]]}}}