Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathogenesis of multiple myeloma (MM) is thought to involve at least two pathways, which generate hyperdiploid (HRD) or nonhyperdiploid (NHRD) tumors, respectively. Apart from chromosome content, the two pathways are distinguished by five primary immunoglobulin heavy chain (IGH) rearrangements (4p16, FGFR3, and MMSET; 6p21, CCND3; 11q13, CCND1; 16q23, MAF; 20q12, MAFB) that are present mainly in NHRD tumors. To determine the prevalence and structures of IGH, immunoglobulin (IG) light chain, and MYC genomic rearrangements in MM, we have done comprehensive metaphase fluorescent in situ hybridization analyses on 48 advanced MM tumors and 47 MM cell lines. As expected, the prevalence of the five primary IGH rearrangements was nearly 70% in NHRD tumors, but only 12% in HRD tumors. However, IGH rearrangements not involving one of the five primary partners, and IG light chain rearrangements, have a similar prevalence in HRD and NHRD tumors. In addition, MYC rearrangements, which are thought to be late progression events that sometimes do not involve an IG heavy or light chain locus, also have a similar prevalence in HRD and NHRD tumors. In contrast to the primary IGH rearrangements, which usually are simple balanced translocations, these other IG rearrangements usually have complex structures, as previously described for MYC rearrangements in MM. We conclude that IG light chain and MYC rearrangements, as well as secondary IGH rearrangements, make similar contributions to the progression of both HRD and NHRD MM tumors.
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PMID:Secondary genomic rearrangements involving immunoglobulin or MYC loci show similar prevalences in hyperdiploid and nonhyperdiploid myeloma tumors. 1838 41

Bortezomib (V) was combined with thalidomide (T) and dexamethasone (D) in a phase I/II trial to determine dose-limiting toxicities (DLT's) and clinical activity of the VTD regimen in 85 patients with advanced and refractory myeloma. The starting dose of V was 1.0 mg/m(2) (days 1, 4, 8, 11, every 21 day) with T added from cycle 2 at 50 mg/day, with 50 mg increments per 10 patient cohorts, to a maximum dose of 200 mg. In the absence of DLT's, the same reiteration of T dose increases was applied with a higher dose of V=1.3 mg/m(2). D was added with cycle 4 in the absence of partial response (PR). Ninety-two percent had prior autotransplants, 74% had prior T and 76% abnormal cytogenetics. MTD was reached at V=1.3 mg/m(2) and T=150 mg. Minor response (MR) was recorded in 79%, and 63% achieved PR including 22% who qualified for near-complete remission. At 4 years, 6% remain event-free and 23% alive. Both OS and EFS were significantly longer in the absence of prior T exposure and when at least MR status was attained. The MMSET/FGFR3 molecular subtype was prognostically favorable, a finding since reported for a VTD-incorporating tandem transplant trial (Total Therapy 3) for untreated patients with myeloma (BJH 2008).
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PMID:VTD combination therapy with bortezomib-thalidomide-dexamethasone is highly effective in advanced and refractory multiple myeloma. 1843 60

MMSET is expressed ubiquitously in early development and its deletion is associated with the malformation syndrome called Wolf-Hirschhorn syndrome. It is involved in the t(4;14) (p16;q32) chromosomal translocation, which is the second most common translocation in multiple myeloma (MM) and is associated with the worst prognosis. MMSET expression has been shown to promote cellular adhesion, clonogenic growth and tumorigenicity in multiple myeloma. MMSET expression has been recently shown to increase with ascending tumor proliferation activity in glioblastoma multiforme. These data demonstrate that MMSET could be implicated in tumor emergence and/or progression. Therefore, we compared the expression of MMSET in 40 human tumor types--brain, epithelial, lymphoid--to that of their normal tissue counterparts using publicly available gene expression data, including the Oncomine Cancer Microarray database. We found significant overexpression of MMSET in 15 cancers compared to their normal counterparts. Furthermore MMSET is associated with tumor aggressiveness or prognosis in many types of these aforementioned cancers. Taken together, these data suggest that MMSET potentially acts as a pathogenic agent in many cancers. The identification of the targets of MMSET and their role in cell growth and survival will be key to understand how MMSET is associated with tumor development.
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PMID:MMSET is overexpressed in cancers: link with tumor aggressiveness. 1912 Dec 87

Multiple myeloma (MM) is an incurable B-cell malignancy characterised by uncontrolled growth and accumulation of malignant plasma cells in the bone marrow. Aberrant expression of CD56 in patients with MM is thought to contribute to a worsened disease course and metastasis. We therefore investigated the regulation of the CD56 promoter in relation to typical clinical factors. We used qPCR and FACS to measure the expression levels of CD56, and potential regulatory factors in patients with MM and related these with MM progression/prognosis. The transcription factors BTBD3, Pax5, RUNX1 and MMSET were positively associated with CD56 expression, as was CYCLIN D1, which is involved in disease progression, anti-apoptosis and proliferation. RUNX1 was negatively associated with the survival of stem-cell transplanted patients. Our findings propose four potential activators of the CD56 promoter and for CD56 to be involved in proliferation and anti-apoptosis, leading to disease progression in MM.
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PMID:Regulation of the CD56 promoter and its association with proliferation, anti-apoptosis and clinical factors in multiple myeloma. 1923 15

The t(4;14) translocation in multiple myeloma (MM) simultaneously dysregulates two apparent oncogenes: fibroblast growth factor receptor 3 (FGFR3) controlled by the 3' immunoglobulin heavy chain enhancer on der(14) and MMSET controlled by the intronic Emu enhancer on der(4). Although all MM tumors and cell lines with a t(4;14) translocation have dysregulated MMSET, about 25% do not express FGFR3. Therefore, the function of dysregulated wild-type (WT) FGFR3 in the pathogenesis of MM remains unclear. We developed a murine transgenic (TG) model in which WT FGFR3 is overexpressed in B lymphoid cells. Although high levels of FGFR3 resulted in lymphoid hyperplasia in about one-third of older mice, no increase in tumorigenesis was observed. However, double TG FGFR3/Myc mice develop mature B lymphoma tumors that occur with a higher penetrance and shorter latency than in single TG Myc mice (P=0.006). We conclude that expression of high levels of WT FGFR3 can be oncogenic and cooperate with MYC to generate B lymphoid tumors. This suggests that dysregulated FGFR3 expression is likely to be essential at least for the early stages of pathogenesis of MM tumors that have a t(4;14) translocation.
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PMID:Ectopic expression of wild-type FGFR3 cooperates with MYC to accelerate development of B-cell lineage neoplasms. 2039 5

Dysregulation of cyclin D2 contributes to the pathogenesis of multiple myeloma, and can occur through translocations that activate MAF/MAFB or MMSET/FGFR3. However, cyclin D2 induction can also be seen in the absence of such translocations, such as in patients with hyperdiploid disease, through unknown mechanisms. In UniGene cluster data-mining and ECgene analysis, we found that zinc-finger with KRAB and SCAN domains 3 (ZKSCAN3), a novel transcription factor, is overrepresented in this malignancy, and three consensus ZKSCAN3 binding sites were found in the cyclin D2 promoter. Analysis of a panel of myeloma cell lines, primary patient samples and datasets from Oncomine and the Multiple Myeloma Genomics Portal (MMGP) revealed expression of ZKSCAN3 messenger RNA (mRNA) in a majority of samples. Studies of cell lines by western blotting, and of primary tissue microarrays by immunohistochemistry, showed ZKSCAN3 protein expression in a majority, and in a manner that paralleled messenger levels in cell lines. ZKSCAN3 overexpression was associated with increased gene copy number or genomic DNA gain/amplification in a subset based on analysis of data from the MMGP, and from fluorescence in situ hybridization studies of cell lines and primary samples. Overexpression of ZKSCAN3 induced cyclin D2 promoter activity in a MAF/MAFB-independent manner, and to an extent that was influenced by the number of consensus ZKSCAN3 binding sites. Moreover, ZKSCAN3 protein expression correlated with cyclin D2 levels in cell lines and primary samples, and its overexpression induced cyclin D2. Conversely, ZKSCAN3 suppression using small hairpin RNAs (shRNAs) reduced cyclin D2 levels, and, importantly, inhibited myeloma cell line proliferation. Finally, ZKSCAN3 was noted to specifically bind to oligonucleotides representing sequences from the cyclin D2 promoter, and to the endogenous promoter itself in myeloma cells. Taken together, the data support the conclusion that ZKSCAN3 induction represents a mechanism by which myeloma cells can induce cyclin D2 dysregulation, and contribute to disease pathogenesis.
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PMID:Evidence of a role for the novel zinc-finger transcription factor ZKSCAN3 in modulating Cyclin D2 expression in multiple myeloma. 2105 42

Multiple myeloma (MM) is a hematological disease caused by malignant proliferation of clonal plasma cells (PCs) known for its clinical and biological heterogeneity. Identification of chromosomal changes in genome of PCs plays a key role in MM pathogenesis and is supposed to have important prognostic significance for MM patients. There are two major genetic entities in MM. Hyperdiploid tumors (H-MM), which include about 50% of MM tumors, often have multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 21 and a substantially lower prevalence of IgH translocations. Nearly half of tumors are non-hyperdiploid (NH-MM), and mostly have one of five recurrent IgH translocations: 11ql13 (CCND1), 6p21 (CCND3), 16q23 (MAF), 20q12 (MAFB), and 4p16 (FGFR3 and MMSET). The development and expanded use of new technologies, such as genome-wide array-based comparative genomic hybridization (aCGH) has accelerated genomic research in MM. This technique is a powerful tool to globally analyze recurrent copy number changes in tumor genome in a single reaction and to study cancer biology and clinical behaviors. It widely overcame routinely used cytogenetic techniques (G-banding, FISH) both in minimal resolution of chromosomal changes and amount of obtained genomic data important for further analyses and clinical applications. Array CGH technique is now used to better understanding of molecular phenotypes, sensitivity to particular chemotherapeutic agents, and prognosis of these diseases. This paper brings brief literature and methodic overview of oligonucleotide-based array-CGH technique in MM diagnosis.
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PMID:Oligonucleotide-based array CGH as a diagnostic tool in multiple myeloma patients. 2192 64

The histone lysine methyltransferase NSD2 (MMSET/WHSC1) is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here, we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation upon t(4;14)-negative cells and promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together, our findings establish H3K36me2 as the primary product generated by NSD2 and demonstrate that genomic disorganization of this canonical chromatin mark by NSD2 initiates oncogenic programming.
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PMID:NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming. 2209 8

Multiple myeloma (MM) is malignancy of isotype-switched, BM-localized plasma cells that frequently results in bone destruction, BM failure, and death. Important molecular subgroups are identified by three classes of recurrent immunoglobulin gene translocations and hyperdiploidy, both of which affect disease course. From a clinical standpoint, it is critical to identify MM patients carrying the t(4;14) translocation, which is present in 15% of myelomas and is associated with dysregulation of WHSC1/MMSET and often FGFR3. These patients should all receive bortezomib as part of their initial induction treatment because this has been shown to significantly prolong survival. In contrast, patients with translocations affecting the MAF family of transcription factors, del17p, or gene-expression profiling (GEP)-defined high-risk disease appear to have a worse prognosis that is not dramatically improved by any intervention. These patients should be enrolled in innovative clinical trials. The remaining patients with cyclin D translocations or hyperdiploidy do well with most therapies, and the goal should be to control disease while minimizing toxicity.
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PMID:Many multiple myelomas: making more of the molecular mayhem. 2216 56

The histone methyltransferase WHSC1 (also known as MMSET) is overexpressed in multiple myeloma (MM) as a result of the t(4;14) chromosomal translocation and in a broad variety of other cancers by unclear mechanisms. Overexpression of WHSC1 did not transform wild-type or tumor-prone primary hematopoietic cells. We found that ACA11, an orphan box H/ACA class small nucleolar RNA (snoRNA) encoded within an intron of WHSC1, was highly expressed in t(4;14)-positive MM and other cancers. ACA11 localized to nucleoli and bound what we believe to be a novel small nuclear ribonucleoprotein (snRNP) complex composed of several proteins involved in postsplicing intron complexes. RNA targets of this uncharacterized snRNP included snoRNA intermediates hosted within ribosomal protein (RP) genes, and an RP gene signature was strongly associated with t(4;14) in patients with MM. Expression of ACA11 was sufficient to downregulate RP genes and other snoRNAs implicated in the control of oxidative stress. ACA11 suppressed oxidative stress, afforded resistance to chemotherapy, and increased the proliferation of MM cells, demonstrating that ACA11 is a critical target of the t(4;14) translocation in MM and suggesting an oncogenic role in other cancers as well.
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PMID:Multiple myeloma-associated chromosomal translocation activates orphan snoRNA ACA11 to suppress oxidative stress. 2275 Nov 2


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