Santra M, Zhan F, Tian E, Barlogie B, Shaughnessy Jr JA subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript. Blood 101: 2374-2376

University of Arkansas at Little Rock, Little Rock, Arkansas, United States
Blood (Impact Factor: 10.45). 04/2003; 101(6):2374-6. DOI: 10.1182/blood-2002-09-2801
Source: PubMed


Previous studies have revealed that that approximately 10% to 15% of multiple myelomas (MMs) are characterized by a reciprocal t(4;14)(p16;q32) translocation that activates expression of FGFR3 and creates an IGH/MMSET fusion transcript. Current data suggest that activation of FGFR3 is the oncogenic consequence of this rearrangement. Using a combination of microarray profiling, reverse transcriptase-polymerase chain reaction (RT-PCR), and interphase fluorescence in situ hybridization (FISH), we show that 32 (18%) of 178 newly diagnosed cases of MM harbor the t(4;14)(p16;q32). Importantly, 32% of these cases lack expression of FGFR3, yet express MMSET and have an IGH/MMSET fusion transcript. Interphase FISH showed that whereas the IGH/MMSET fusion was present in more than 80% of the clonotypic plasma cells in these novel cases, there was typically a complete loss of one copy of FGFR3. These data indicate that the t(4;14)(p16;q32) and loss of FGFR3 occurred at a very early stage and suggest that activation of MMSET, not FGFR3, may be the critical transforming event of this recurrent translocation.

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Available from: Madhumita Santra, May 29, 2014
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    • "The t(4; 14) translocation leads to the simultaneous overexpression of two genes, FGFR3 (fibroblast growth factor receptor 3) and MMSET. FGFR3 has transforming activity in vitro and in vivo, but approximately 30% of t(4; 14) MM patients do not express FGFR3, whereas overexpression of MMSET isoforms is a universal feature of t(4; 14) cases [12, 17, 18]. Furthermore, the poor prognosis of t(4; 14) persists irrespective of FGFR3 expression [12]. "
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    ABSTRACT: Recurrent chromosomal translocations are central to the pathogenesis, diagnosis, and prognosis of hematologic malignancies. The translocation t(4; 14)(p16; q32) is one of the most common translocations in multiple myeloma (MM) and is associated with very poor prognosis. The t(4; 14) translocation leads to the simultaneous overexpression of two genes, FGFR3 (fibroblast growth factor receptor 3) and MMSET (multiple myeloma SET domain), both of which have potential oncogenic activity. However, approximately 30% of t(4; 14) MM patients do not express FGFR3 and have poor prognosis irrespective of FGFR3 expression, whereas MMSET overexpression is universal in t(4; 14) cases. In this review, we provide an overview of recent findings regarding the oncogenic roles of MMSET in MM and its functions on histone methylation. We also highlight some of MMSET partners and its downstream signalling pathways and discuss the potential therapeutics targeting MMSET.
    BioMed Research International 07/2014; 2014:636514. DOI:10.1155/2014/636514 · 1.58 Impact Factor
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    • "15–20% pacjentów ze SzP [37], należy do grupy aberracji związanych z położonym na chromosomie 14 regionem kodującym ciężki łańcuch immunoglobulin (IgH). Region ten jest transkrypcyjnie aktywny w limfocytach B, dlatego uważa się, że translokacja potencjalnych onkogenów w jego locus może mieć znaczący udział w patogenezie większości nowotworów B-komórkowych, w tym SzP [38] Zaobserwowano , że u wszystkich pacjentów z t(4;14) w komórkach plazmatycznych występuje nadekspresja onkogenu białkowej domeny MMSET, a u 70% także onkogenu FGFR3 [39] [40]. Wyniki przeprowadzonych w ostatnich latach badań wskazują na udział MMSET w regulacji naprawy DNA oraz ogólnej ekspresji genów [41]. "
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    ABSTRACT: A remarkable progress, which has been made during the last two decades in the multiple myeloma (MM) treatment, is mainly associated with the introduction to MM therapy three new drugs - thalidomide, lenalidomide and bortezomib. Global improvement of prognosis in MM, confirmed by numerous clinical trials and epidemiological studies, is mainly a consequence of very favorable results obtained in patients in the standard-risk group. However, in patients affected by prognostically unfavorable chromosomal aberrations, who constitute approximately 25% of all MM patients, only a slight improvement in the prognosis has become possible. Interestingly, the effectiveness of various new drugs for patients in the high-risk group appears to be different. The results of clinical trials indicate that currently bortezomib seems to be the most effective drug for patients with unfavorable cytogenetic abnormalities, especially patients with translocation t(4;14). In the present article the published data on the efficacy of bortezomib in first-line therapy in patients with unfavorable cytogenetic abnormalities are reviewed. The principles of risk stratification and individualization of therapy in MM are also discussed.
    Acta haematologica Polonica 07/2014; 45(3). DOI:10.1016/j.achaem.2014.06.002
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    • "The upregulation of FGFR3 results in the ectopic expression of the FGFR3 tyrosine kinase receptor, an aberration with a currently unclear role in myelomagenesis. Interestingly, the pathogenic role of FGFR3 is somewhat in question, as approximately 30% of í µí±¡(4; 14) tumours are imbalanced and lack FGFR3 expression due to loss of the derivative 14 chromosome [28] [32]. Furthermore, in these 30% lacking FGFR3 expression, the adverse prognosis of í µí±¡(4; 14) remains [28], lending support for the role of the second gene MMSET. "
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    ABSTRACT: Multiple myeloma is a malignant proliferation of monoclonal plasma cells leading to clinical features that include hypercalcaemia, renal dysfunction, anaemia, and bone disease (frequently referred to by the acronym CRAB) which represent evidence of end organ failure. Recent evidence has revealed myeloma to be a highly heterogeneous disease composed of multiple molecularly-defined subtypes each with varying clinicopathological features and disease outcomes. The major division within myeloma is between hyperdiploid and nonhyperdiploid subtypes. In this division, hyperdiploid myeloma is characterised by trisomies of certain odd numbered chromosomes, namely, 3, 5, 7, 9, 11, 15, 19, and 21 whereas nonhyperdiploid myeloma is characterised by translocations of the immunoglobulin heavy chain alleles at chromosome 14q32 with various partner chromosomes, the most important of which being 4, 6, 11, 16, and 20. Hyperdiploid and nonhyperdiploid changes appear to represent early or even initiating mutagenic events that are subsequently followed by secondary aberrations including copy number abnormalities, additional translocations, mutations, and epigenetic modifications which lead to plasma cell immortalisation and disease progression. The following review provides a comprehensive coverage of the genetic and epigenetic events contributing to the initiation and progression of multiple myeloma and where possible these abnormalities have been linked to disease prognosis.
    Advances in Hematology 04/2014; 2014(6):864058. DOI:10.1155/2014/864058
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