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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monoclonal gammopathy of undetermined significance (MGUS) is a frequent condition in patients over 50 years old, that ultimately leads to multiple myeloma (MM) in 20% of patients after 20 to 35 years of follow-up. Little is known about cytogenetic changes associated with this condition. We studied 19 MGUS patients both at diagnosis and after 12 to 35 months of follow-up (mean = 26), using DNA content measurement of bone marrow plasma cells (BMPC), and a new interphase fluorescence in situ hybridization technique (FISH) allowing the simultaneous identification of monotypic BMPC (fluorescent anti light-chain antibodies) and the determination of the number of copies for two different chromosomes within the same PC nucleus (one biotin-labeled probe coupled next to texas red avidin and one FITC-labeled probe). At diagnosis of the MGUS, single interphase FISH showed at least one numeric chromosome change in 13 of 19 patients, after the use of centromeric probes directed against chromosomes no. 3, no. 7, no. 9, and no. 11. At follow-up, abnormalities found at diagnosis in 13 patients were still shown. Moreover, abnormalities occurred in three of the last six patients (trisomy for one to three different chromosomes), although no patient evolved into MM. Dual interphase FISH showed that some BMPC bore numeric changes with both probes tested whereas other BMPC bore abnormality with only one of the probes tested. In patients who showed trisomy for at least three different chromosomes, distribution of numeric changes within BMPC defined significant numbers of up to seven different BMPC clones. All these various clones were shown both at diagnosis and at follow-up. In every patient, these various clones differed only for the number of abnormalities they exhibited, and could be related to each other in a model of gradual acquisition of chromosome changes. Eventually, data reported here show that MGUS patients acquire slowly, gradually, but ineluctably chromosome changes, distributed within several related subclones. However, these changes are not related to transformation into MM: among the various clones coexisting within the same patient, a peculiar change, still to demonstrate, might develop and lead to overt MM.
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PMID:Several cytogenetic subclones may be identified within plasma cells from patients with monoclonal gammopathy of undetermined significance, both at diagnosis and during the indolent course of this condition. 934 53

Chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus at chromosome 14q32 represent a common mechanism of oncogene activation in lymphoid malignancies. In multiple myeloma (MM), the most consistent chromosomal abnormality is the 14q+ marker, which originates in one third of cases through a t(11; 14)(q13; q32) chromosomal translocation; in the remaining cases, the identity of the partner chromosomes has not been well established. We used a Southern blot approach based on the linkage analysis of the joining (J) and the constant (C) mu, alpha, and gamma regions to detect cases bearing IGH switch-mediated chromosomal translocations. We evaluated DNA of 88 nonkaryotyped patients with MM (78 cases) or plasma cell leukemia (PCL) (10 cases) and found the presence of "illegitimate" rearranged IGH fragments (no comigration between the J and C regions) in 21 cases. To confirm this analysis, we cloned the illegitimate rearranged fragments from three samples, and the molecular and fluorescent in situ hybridization (FISH) analyses indicated the presence of chromosomal translocations juxtaposing a switch IGH region to sequences from chromosomes 11q13 (one PCL case) or 4p16.3 (two MM cases). Interestingly, the breakpoints on 4p16.3 occurred about 14 kb apart in a genomic region located approximately 50 kb centromeric to the fibroblast growth-factor receptor 3 (FGFR3) gene. Moreover, Southern blot analysis using 4p16.3 genomic probes detected a rearrangement in an additional MM tumor. FISH analysis of the MM-derived KMS-11 cell line, reported to be associated with a t(4; 14)(p16.3; q32), showed that the FGFR3 gene was translocated on 14q32. High levels of FGFR3 mRNA expression were observed in the cloned MM tumors and KMS-11 cell line, but not in the cases that were apparently negative for this lesion. Furthermore, a point mutation at codon 373 in the transmembrane domain of the FGFR3 gene resulting in an amino acid substitution (Tyr --> Cys) was detected in the KMS-11 cell line. These findings indicate that the t(4; 14)(p16.3; q32) represents a novel, recurrent chromosomal translocation in MM, and suggest that the FGFR3 gene may be the target of this abnormality and thus contribute to tumorigenesis in MM.
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PMID:A novel chromosomal translocation t(4; 14)(p16.3; q32) in multiple myeloma involves the fibroblast growth-factor receptor 3 gene. 976 94

Karyotypes in multiple myeloma (MM) are complex and exhibit numerous structural and numerical aberrations. The largest subset of structural chromosome anomalies in clinical specimens and cell lines involves aberrations of chromosome 1. Unbalanced translocations and duplications involving all or part of the whole long arm of chromosome 1 presumably occur as secondary aberrations and are associated with tumor progression and advanced disease. Unfortunately, cytogenetic evidence is scarce as to how these unstable whole-arm rearrangements may take place. We report nonrandom, unbalanced whole-arm translocations of 1q in the cytogenetic evolution of patients with aggressive MM. Whole-arm or "jumping translocations" of 1q were found in 36 of 158 successive patients with abnormal karyotypes. Recurring whole-arm translocations of 1q involved chromosomes 5,8,12,14,15,16,17,19,21, and 22. A newly delineated breakpoint present in three patients involved a whole-arm translocation of 1q to band 5q15. Three recurrent translocations of 1q10 to the short arms of different acrocentric chromosomes have also been identified, including three patients with der(15)t(1;15)(q10;p10) and two patients each with der(21)t(1;21)(q10;p13) and der(22)t(1;22) (q10;p10). Whole-arm translocations of 1q10 to telomeric regions of nonacrocentric chromosomes included der(12)t(1;12) (q10;q24.3) and der(19)t(1;19)(q10;q13.4) in three and two patients, respectively. Recurrent whole-arm translocations of 1q to centromeric regions included der(16)t(1;16)(q10;q10) and der(19)t(1;19)(q10;p10). The mechanisms involved in the 1q instability in MM may be associated with highly decondensed pericentromeric heterochromatin, which may permit recombination and formation of unstable translocations of chromosome 1q. The clonal evolution of cells with extra copies of 1q suggests that this aberration directly or indirectly provides a proliferative advantage.
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PMID:Jumping translocations of chromosome 1q in multiple myeloma: evidence for a mechanism involving decondensation of pericentromeric heterochromatin. 947 40

Dysregulation of oncogenes by translocation to an IgH (14q32) or IgL (kappa, 2p11 or lambda, 22q11) locus is a frequent event in the pathogenesis of B-cell tumors. Translocations involving an IgH locus and a diverse but nonrandom array of chromosomal loci occur in most multiple myeloma (MM) tumors even though the translocations often are not detected by conventional cytogenetic analysis. In a continuing analysis of translocations in 21 MM lines, we show that the novel, karyotypically silent t(14;16)(q32.3;q23) translocation is present in 5 MM lines, with cloned breakpoints from 4 lines dispersed over an approximately 500-kb region centromeric to the c-maf proto-oncogene at 16q23. Another line has a t(16;22)(q23;q11), with the breakpoint telomeric to c-maf, so that the translocation breakpoints in these 6 lines bracket c-maf. Only these 6 lines overexpress c-maf mRNA. As predicted for dysregulation of c-maf by translocation, there is selective expression of one c-maf allele in 2 informative lines with translocations. This is the first human tumor in which the basic zipper c-maf transcription factor is shown to function as an oncogene.
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PMID:Frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma. 961 39

Previously we reported that a karyotypically silent t(4;14)(p16. 3;q32.3) translocation is present in about 25% of multiple myeloma (MM) tumors, and causes overexpression of FGFR3, which is 50 to 100 kb telomeric to the 4p16 breakpoints. Frequent FGFR3 kinase activating mutations in MM with t(4;14) translocations substantiate an oncogenic role for FGFR3. We now report that the 4p16 breakpoints occur telomeric to and within the 5' introns of a novel gene, MMSET (Multiple Myeloma SET domain). In normal tissues, MMSET has a complex pattern of expression with a short form (647 amino acids [aa]) containing an HMG box and hath region, and an alternatively spliced long form (1365 aa) containing the HMG box and hath region plus 4 PHD fingers and a SET domain. Although t(4;14) translocation results in IgH/MMSET hybrid transcripts, overexpression of MMSET also occurs from endogenous promoters on 4p16. Given the homology to HRX/MLL1/ALL1 at 11q23 that is dysregulated by translocations in acute leukemia, we hypothesize that dysregulation of MMSET contributes to neoplastic transformation in MM with t(4;14) translocation. This is the first example of an IgH translocation that simultaneously dysregulates two genes with oncogenic potential: FGFR3 on der(14) and MMSET on der(4).
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PMID:The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. 1151 Apr 69

The effect of high-dose irradiation on telomerase activity was examined in some human lymphoma (DL40, DL95, DL110) and myeloma (U266) cell lines. The survival rate was reduced in DL40, DL110 and U266 by irradiation. Irradiation, however, showed no effect on the rate of DL95. Telomerase activity was detected in non-irradiated samples of all cell lines, as measured by PCR-based telomeric repeat amplification protocol assay. The telomerase activity increased 2-6.5 fold by irradiation. Especially in DL110, the activation increased in a dose-dependent manner. In the early phase after irradiation, we observed no correlation between telomerase activity and cell viability, suggesting that telomerase-mediated chromosome healing might not be a major cause and/or not sufficiently effective to protect the cells from irradiation.
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PMID:Effects of irradiation on telomerase activity in human lymphoma and myeloma cell lines. 985 53

To gain insight into the real incidence of the numeric chromosomal aberrations and the cell lineage involvement of the neoplastic process in multiple myeloma (MM), we examined 18 Chinese MM patients by May-Grunwald-Giemsa (MGG) staining and fluorescence in situ hybridization using three DNA centromeric probes specific for chromosomes 3, 7, and 9. In this investigation, cytogenetic abnormalities were detected in plasma cells (PCs), myeloid cells (MCs), and lymphoid cells (LCs) in all of the MM patients studied. This is the first demonstration of the cytogenetic aberration involved in the myeloid series. Furthermore, the MCs and PCs of 16 MM patients had the same aneuploidies in one or more of the chromosomes analyzed. These data suggest that the neoplastic transformation of MM may occur early in the hematopoietic development. Chromosomal aberrations involving mainly subclones and considerable cellular heterogeneity with gain of a variety of copy numbers of the same chromosome were demonstrated within PCs, which may possibly be the result of an underlying defect of PCs in the control of their number of chromosomes. Whereas PCs showed evidence suggestive of increased polyploidization, MCs and LCs, which exhibited similar chromosomal patterns as the former, rarely did. Thus, the clonal evolution from LC to PC, if that happens in MM, is characterized by chromosomal instability favoring growth of tumor cells with polysomies and polyploidies.
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PMID:Combined morphological and interphase fluorescence in situ hybridization study in multiple myeloma of Chinese patients. 991 13

Deletions or monosomy of chromosome 13 are frequent in multiple myeloma (MM). A candidate tumor suppressor gene might reside telomeric of the retinoblastoma gene (RBl) at band 13q14 and to play a role in B cell neoplasm. The D13S319 locus, between RB1 and D13S25 loci at 13q14 is the most commonly deleted marker in chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). We evaluated the D13S319 locus in 24 MM cases by fluorescence in situ hybridization (FISH). We observed monosomy for D13S319 in 6/20 (30%) MM patients with an apparently normal karyotype. As expected, in four karyotypically abnormal MM cases with partial or complete monosomy for chromosome 13, all of them had monoallelic loss of D13S319. Our results indicated that the loss of D13S319 is commonly found in MM, even at diagnosis, and is more frequent than predicted based on conventional cytogenetic analysis of metaphase spreads. This finding implicates a candidate tumor suppressor gene at 13q14 in the pathogenesis of MM.
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PMID:Frequent monoallelic loss of D13S319 in multiple myeloma patients shown by interphase fluorescence in situ hybridization. 1004 44

In many B-cell malignancies, 14q32.3 chromosomal rearrangements involving the immunoglobulin heavy chain (IgH) locus have been shown to be pathognomonic for the disease. Although in myeloma heterogeneous and complex karyotypes are found, 14q32.3 translocations are prominent. However, owing to the telomeric position of the IgH locus, 14q32.3 translocations may be easily missed. We established fluorescence in situ hybridization (FISH) assays on chromosomes and DNA fibers to determine both the occurrence of 14q32.3 rearrangements in myeloma cell lines and the precise localization of the breakpoints in the IgH locus. Our results show that 14q32.3 chromosomal rearrangements are present in almost every myeloma cell line analyzed (17 of 19, 89%). Breakpoint analysis of the lines harboring one or more 14q32.3 rearrangements with the use of fiber-FISH revealed the involvement of switch regions in the IgH locus in 11 of 17 cell lines. Remarkably, pseudogamma genes without switch regions were involved in 3 of 17 cell lines, all derived from IgA myelomas. Three of 17 cell lines contained breakpoints outside a switch or immunoglobulin heavy chain constant region. The almost ubiquitous presence of 14q32.3 rearrangements suggests an obligatory role in the development of myeloma. The high incidence of breakpoints involving switch regions indicates an oncogenic event in a late stage of B-cell differentiation.
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PMID:Fluorescence in situ hybridization analysis shows the frequent occurrence of 14q32.3 rearrangements with involvement of immunoglobulin switch regions in myeloma cell lines. 1008 40

Fluorescence in situ hybridization (FISH) on interphase nuclei has been shown to be an efficient method for detecting aneuploidy in multiple myeloma (MM). The aim of this study was to test the feasibility of FISH techniques for detecting malignant cells in the harvests of MM patients submitted to autologous transplantation. As trisomy 9 (T9) is a frequent event in MM, we used it as a genetic marker of malignant plasma cells. T9 was detected in 45 out of 55 MM bone marrow samples (81.8%) using a chromosome 9 centromeric (C9C) probe. Twenty-four of the 55 MM patients were subjected to high-dose therapy followed by autologous unselected progenitor cell transplantation. Trisomy 9 was detected in 20 patients and was used as a marker of malignant cells. Upon karyotypic analysis, three of the four remaining patients without T9 showed an unbalanced translocation leading to a complete trisomy of the long arm of chromosome 1 (T1q). We thus used a 1q juxtacentromeric probe, pUC1.77, as another genetic marker of malignant plasma cells in these three further patients. FISH with C9C or pUC1.77 probes was performed on the harvests of these 23 patients and detected clonal cells in 11 transplants. The disease-free survival from graft was significantly longer for the patients who had no malignant cells in their transplant (P=0.009). The median disease-free survival was 23 months in these patients, as compared to 12 months in the patients whose transplant was contaminated. As almost all MM are cytogenetically abnormal, FISH with adequate probes represents a simple, quantitative tool for rapid detection of malignant cells in the harvests. Our results also suggest that the presence of MM cells in the transplant may be predictive of poor outcome.
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PMID:Interphase FISH: a rapid method for detecting malignant plasma cells in multiple myeloma patients submitted to autologous transplantation. 1021 45


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