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Blood, 1 September 2006, Vol. 108, No. 5, pp. 1426-1427. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sonneveld, P. Search for Related Content PubMed Articles by Sonneveld, P. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Comment on Hanamura et al, page 1724 Gain of 1q21 in multiple myeloma: from bad to worse? Pieter Sonneveld ERASMUS MC Recurrent chromosomal aberrations occur in the majority of multiple myeloma cases and may have strong clinical implications. In this issue of Blood, Hanamura and colleagues describe the frequent gain of chromosome 1q21, which is associated with poor-prognosis multiple myeloma. The genome of clonal multiple myeloma (MM) plasma cells is characterized by recurrent chromosomal translocations. While the mechanism of initiation of plasma cell dyscrasias is unknown, myeloma is thought to develop through a multistep process in which clonal selection and additional mutations are relevant for disease progression. Deletion of chromosome 13 as well as hypodiploidy and t(4;14) with dysregulated expression of MMSET/FGFR3 can be recognized as disease entities and they are associated with a poor prognosis.1 As in many other cancers, rearrangements and changes of chromosome 1 are prevalent in multiple myeloma, and deletions of 1p and gains of 1q are frequently observed. Comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) have revealed chromosomal gains of 1q, which may occur as iso-chromosomes, duplications, or jumping translocations. In addition, single-nucleotide polymorphism (SNP)-based mapping arrays have identified copy number changes of 1q at the submegabase level and loss of heterozygosity.2 In many cases, loss of heterozygosity is a major mechanism leading to expression of mutant genes. The DNA sequence and biologic annotation of chromosome 1 were recently published.3 Since chromosome 1 has 3141 genes, is one of the largest chromosomes, and has many overlapping coding sequences, it is a likely candidate for genetic events that lead to malignant transformation. In this issue of Blood, Hanamura and colleagues demonstrate that the frequency of 1q21 amplifications is low in monoclonal gammopathy of undetermined significance (MGUS) and increases to 43% in the transition to overt multiple myeloma and 72% at relapse. Amplifications of 1q21 are concurrent with dysregulated expression of c-MAF, MMSET/FGFR3, or Del13 and are associated with a more aggressive clinical course of the disease. Their findings suggest that myeloma cells with more than 4 copies of 1q21 are associated with a drug-resistant phenotype. A recently presented analysis of the patients in the French Intergroupe Francophone du Myélome (IFM) trials did however not find an independent prognostic impact of 1q gains.4 The clinical translation of this finding is as yet questionable, since patients with amplifications of 1q21 do not benefit from alternative therapeutic strategies such as thalidomide. View larger version (35K): [in this window] [in a new window]   The proportion of cells with Amp1q21 at diagnosis and relapse. See the complete figure in the article beginning on page 1724.   The cellular and molecular mechanisms of 1q21 amplifications are not well understood. Previous studies suggested that CKS1B, BCL-9, or RAB25 may be crucial genes in 1q21-amplified cases, which could not be confirmed by others.2 The same investigators have suggested that CKS1B, which regulates proteolysis of the cyclin-dependent kinase inhibitor p27KIP1, is a candidate gene for myeloma progression.5 Finally, these data indicate the relevance of karyotypic and molecular analysis in patients with multiple myeloma. If indeed amplifications of 1q21 represent an independent unfavorable prognostic factor, new treatments are needed, since these patients do not benefit from recent improvements such as adding thalidomide to high-dose treatment. Since 1q21 amplification occurs in almost 50% of the patients, its relevance should then be evaluated in clinical trials with new antimyeloma drugs. References Fonseca R, Blood E, Rue M, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood. 2003;101: 4569-4575.[Abstract/Free Full Text] Walker BA, Leone PE, Jenner MW, et al. Integration of global SNP-based mapping and expression arrays reveals key regions, mechanisms and genes important in the pathogenesis of multiple myeloma. Blood. Prepublished on May 16, 2006, as DOI 10.1182/blood-2006-02-005496.[Abstract/Free Full Text] Gregory SG, Barlow KF, McLay KE, et al. The DNA sequence and biological annotation of human chromosome 1 Nature. 2006;441: 315-321.[CrossRef][Medline] [Order article via Infotrieve] Avet Loiseau H, Attal M, Moreau P, et al. A comprehensive analysis of cytogenetic abnormalities in myeloma: results of the FISH analysis of 1000 patients enrolled in the IFM99 trials [abstract]. Blood. 2005; 106. Abstract 622. Shaughnessy J. Amplification and overexpression of CKS1B at chromosome band 1q21 is associated with reduced levels of p27Kip1 and an aggressive clinical course in multiple myeloma. Hematology. 2005;10(suppl 1): 117-126. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation Ichiro Hanamura, James P. Stewart, Yongsheng Huang, Fenghuang Zhan, Madhumita Santra, Jeffrey R. Sawyer, Klaus Hollmig, Maurizio Zangarri, Mauricio Pineda-Roman, Frits van Rhee, Federica Cavallo, Bart Burington, John Crowley, Guido Tricot, Bart Barlogie, and John D. Shaughnessy, Jr Blood 2006 108: 1724-1732. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sonneveld, P. Search for Related Content PubMed Articles by Sonneveld, P. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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