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NEOPLASIA
From the Division of Hematology and Department of
Internal Medicine, Department of Laboratory Medicine and Pathology,
Mayo Clinic, Rochester, MN.
Translocations involving immunoglobulin (Ig) loci and chromosome 13 monosomy ( Chromosomal translocations involving 14q32 are
thought to be early events in the pathogenesis of many B-cell
neoplasias,1,2 including multiple myeloma (MM). Nearly all
MM cell lines harbor chromosome translocations involving the
immunoglobulin H (IgH) locus, which are believed to originate from
errors at the time of isotype-class switching.3-8 These
translocations involve an array of nonrandom, recurrent, partner
chromosome that includes, among others, loci 4p16.3, 11q13, and
16q23.3-8 These translocations result in dysregulation of
putative oncogenes, including cyclin D1/myeov (11q13),
c-maf (16q23), FGFR3/MMSET (4p16.3),
and MUM-1 (6p25), among others.3-5,9 The
estimated prevalence of IgH translocations for patients with MM is
close to 60% when fluorescence in situ hybridization (FISH) is used to
study interphase nuclei.10,11 The overexpression of these
oncogenes (mostly proliferation genes) is thought to promote cell
division and cause immortalization of neoplastic plasma cells (PCs).
Monoclonal gammopathy of undetermined significance (MGUS) is a
precursor state to MM and thought to have similar cytogenetic abnormalities as clonal PCs of MM, including IgH
translocations.11 Avet-Loiseau et al12
reported that 46% of patients with MGUS (36 of 79) have translocations
involving the IgH locus. They found that t(11;14)(q13;q32) is the most
common translocation in MGUS and is present in about one sixth of
patients. However, they rarely observed a t(4;14)(p16.3;q32). We have
found t(11;14)(q13;q32) to be prevalent in the clonal PCs of patients
with a related condition, light-chain amyloidosis (AL).13
More recently, Malgeri and colleagues14 detected
t(4;14)(p16.3;q32) in 1 of 16 patients with MGUS by reverse transcriptase-polymerase chain reaction for the IgH-multiple myeloma SET domain (MMSET) transcript. In addition, Perfetti et
al15 used the same method to detect t(4;14)(p16.3;q32)
transcripts in 14% of patients with AL. No systematic study of
translocations involving IgL- PCs are, by definition, rare in bone marrow (BM) samples of patients
with MGUS.23 To improve the sensitivity of the interphase FISH method, we used simultaneous immunofluorescent detection of the
cytoplasmic light chains and cytomorphology (cIg-FISH)24 to
analyze clonal PCs. The purpose of this study of MGUS patients was to determine the presence and frequency of translocations involving IgH and IgL- Patients and BM samples
Slide preparation and interphase FISH
Probes Break-apart strategy (segregation).
The probes used in these experiments were directly labeled via nick
translation with either SpectrumGreen or SpectrumRed (Vysis, Downers
Grove, IL) (Figure 1). For the
IgH segregation ("break-apart") strategy we used both a bacterial
artificial chromosome (BAC) clone for the constant region of
the IgH locus (CH, labeled with SpectrumGreen) and a cosmid
clone for the IgH variable region (VH, labeled with
SpectrumRed) (Figure 1).13,27 For the IgL-
Fusion strategy (colocalization). For detection of translocation fusion signals, we used probes for 4p16.3, 11q13, and 16q23 (labeled with SpectrumRed); that bracket all reported breakpoints in the human MM cell lines, along with the VH and CH probes (labeled with SpectrumGreen). For the 11q13 region, we used a contig of probes spanning approximately 100 kilobases (kb) telomeric and 600 kb centromeric to the cyclin D1 gene (all directly labeled in SpectrumRed; Vysis).28-30 This pool contained the cosmids cCL11-505, cCL11-44, and cCL11-356 (provided by K. Hashimoto, Japanese Collection of Research Bioresources, Tokyo, Japan), cos3.62 and cos3.91 (provided by Ed Schuuring at Leiden University, The Netherlands), and the P1 clones ICRF 700 B1587 and ICRF 700 J077 (provided by R. Kochan, Resource Center and Primary Database [RZDP], Berlin, Germany). For the 4p16.3 region, we used the cosmid probes described in detail by Chesi et al4 and spanning a total of approximately 200 kb and encompassing all reported 4p16.3 breakpoints in human MM cell lines. For the detection of translocations involving 16q23, we used 2 clones obtained from a BAC library (clones 356D21 and 484H2; Research Genetics, Huntsville, AL) and the BAC clones 10205 and 10206, as described by Chesi et al.5 The clone 356D21 (120 kb) is located centromeric to 484H2 (95 kb), and both are separated approximately 500 kb apart (both are centromeric to c-maf). Ploidy and Normal and abnormal signal patterns The normal signal pattern for IgH (CH/VH) and IgL-
(V /C) break-apart strategies was 2 pairs
of closely related green/red signals (Figure 1).13 The
presence of segregating signals was considered evidence of an IgH or
IgL- translocation.
For the translocation fusion strategies, the normal pattern was 2 red, 2 green signals, and no fusions (Figure 1). The presence of fusion signals arising from one of the participating chromosomes (2R1G1F, 2R2G2F, 1R1G1F, or 1R2G1F, 1R1G2F) was considered evidence of a translocation (Figure 1). Probe validation and normal range Before doing this investigation, we studied normal metaphases to establish that the probes hybridized to the correct chromosomal loci, and we found no cross-hybridization to inappropriate loci. We also did separate hybridization experiments on specimens known to have either t(11;14)(q13;q32) (clinical samples), t(4;14)(p16.3;q32) (cell line KMS11), or t(14;16)(q32;q23) (cell lines OCI-MY5, JJN3, and MM.1) to confirm that these probes could accurately detect these specific translocations. We tested these probes on normal cells to establish the incidence of nuclei with false-positive signal patterns: The upper limit of normal plus 3 SD proved to be 9%. We attempted to count as many PCs as possible (> 20 in all samples). However, to further improve the stringency of our criteria and because of the uncertain biologic significance of patients with low percentages of abnormal PCs, we used the following cutoff values: Less than 10% of cells with an abnormal pattern indicated no translocation, 10% to 24% abnormal cells was an equivocal result, and 25% or more abnormal cells indicated a translocation. For the 13 assay we used our previously
determined upper limit of normal ( 10% is indicative of 13) to
discern samples with and without the abnormality.31,32 We
previously reported the normal range for cells that are aneuploid by
the cIg-FISH strategy.24
Scoring The scoring process included a cytomorphologic assessment to exclude non-PCs with cIg positivity, including lymphocytes and monocytes, and we attempted to score only the cIg-positive PCs. A decision to score a cell was made a priori using the 4,6-diamidino-2-phenylindole (DAPI) filter to assess cell morphology. If at least one signal of each probe was observed, the cell was scored.Immunohistochemistry and immunofluorescence Immunohistochemical detection of cyclin D1 up-regulation was done on paraffin-embedded BM core biopsy samples as previously described by Hoyer et al.33 A sample was considered positive if the PCs had nuclear positivity (± cytoplasmic stain). Immunofluorescent detection of fibroblast growth factor-receptor 3 (FGFR3) up-regulation was performed on cytospin slides as reported by Chesi et al.34 A sample was considered positive if it displayed strong cytoplasmic staining.
Patient demographics Seventy-two patients were studied. The medical history of each patient met the criteria for the diagnosis of MGUS or SMM.23 All patients had a monoclonal protein in the serum detected by protein electrophoresis and/or immunofixation ( = 42,
= 30). Patients were not eligible for this study if they had
evidence of MM complications. All MGUS patients had discrete clonal
proliferations of PCs (< 10%) in their BM as detected by PC labeling
index (PCLI) or aspirate. The median value of the monoclonal protein on
the serum protein electrophoresis was 13.5 g/L [1.35 g/dL] (range immunofixation only to 35 g/L [3.5 g/dL]). Nine patients had
a monoclonal protein that could only be detected by immunofixation. The
isotypes were as follows: 64 patients had an IgG protein, 4 had IgA,
and 4 had light-chain-only disease (idiopathic Bence-Jones proteinemia). The distribution of isotypes is similar to what has been
described for other MGUS series, with only a slight lower proportion of
cases with a monoclonal IgA protein.23 This can have some,
albeit minor, influence on the prevalence of the specific chromosomal
abnormalities observed because they are thought to correlate with
heavy-chain isotype usage.
IgH and IgL- locus was
observed in 30 (49%) of 61 patients (Tables
1,2). A translocation specifically
involving the IgH locus was seen in 27 (46%) of 59 patients. The
median percentage of abnormal PCs was 57% (range, 27%-100%). A total
of 14 patients had equivocal results for a translocation involving the
IgH locus and no other definitive translocation (Table
3).
Translocations involving the IgL- locus were seen in 4 (11%) of 37 patients. The median percentage of abnormal PCs was 63% (range,
25%-90%). Another 3 patients had equivocal results for a
translocation involving the IgL- locus. Altogether, 47 (77%) of 61 patients had evidence of a definitive or equivocal result for an IgH
translocation. There was no significant difference in the
prevalence of the translocation between patients with samples that were
enriched versus not (P > .2) and between patients in whom
the abnormality was detected by immunofixation only versus those that
had a measurable monoclonal protein (P > .2).
Specific partners and disease progression Fifteen (25%) of 59 patients had evidence of a t(11;14)(q13;q32) (21 [36%] of 59 if equivocals were included) (Table 1). The median percentage of abnormal PCs was 64% (range, 25%-100%). None of these patients progressed since the time of translocation detection (range, 0-52 months) or diagnosis (range, 0-55 months). Five (9%) of 56 patients had a t(4;14)(p16.3;q32) detected (7 [13%] of 56 if equivocals included) (Figure 1). Four of these 5 patients had a predominant pattern of only 1 fusion signal. These 5 patients were followed for 6.5 to more than 14 months since the time of translocation detection, 21 to 58 months since the time MGUS was diagnosed, and had no evidence of disease progression. The median percentage of abnormal PCs was 79% (range, 37%-100%). Three (5%) of 58 patients had the t(14;16)(q32;q23) detected in 25%, 50%, and 100% of PCs (Figure 1). Two of these patients had a predominant pattern of only 1 fusion signal. These patients have been followed for 7 to 25 months since the time of translocation detection, for 24 to 66 months since the time MGUS was diagnosed, and had no evidence of disease progression.Two patients had clear evidence of 2 IgH translocations (Table 1). One patient had 91% of the cells with a t(4;14)(p16.3;q32) fusion abnormality pattern, while there were also 30% of cells with a t(11;14)(q13;q32). This patient had 2 subclones detected in the IgH break-apart strategy; 70% of the cells had 1 red, 1 green, and 1 fusion pattern, while 30% of the cells had a 2 reds, 1 green, and 1 fusion pattern. Presumptively. the t(11;14)(q13;q32) represents a secondary rearrangement in a clone already established with a t(4;14)(p16.3;q32). Another patient had 100% of the cells with t(4;14)(p16.3;q32) and 100% of cells with a t(14;16)(q32;q23). There was one predominant pattern in the IgH break-apart strategy: 1 red, 1 green, and 1 fusion. Chromosome 13 abnormalities The13 was detected in 24 (50%) of 48 patients using the
standard cutoff criterion. If we used the same and more stringent criterion for IgH translocations ( 25% abnormal cells), we still found the abnormality at high prevalence (19 [40%] of 48 cases). In
all cases both signals were simultaneously deleted, likely indicating a
large deletion or monosomy, as we and others have reported for
MM.31,35 The median percentage of abnormal PCs was 91%
(range, 10%-100%). Patients with t(11;14)(q13;q32) (7 of 12 patients,
P > .2) or IgL- (1 of 3, P > .2) were
equally likely to have 13 but not those with t(4;14)(p16.3;q32),
where 13 appeared to be more prevalent (3 of 4 patients).36 No meaningful information was available for
patients with the t(14;16)(q32;q23).
Biologic and prognostic variables Each of the chromosomal abnormalities was correlated with laboratory biologic and prognostic variables of MM (serum monoclonal protein concentration, hemoglobin, creatinine, 2-microglobulin, BM PC%, and PCLI). Given the small
number of patients, no specific clinical and biologic features could be
established, although there was a suggestion that patients with 13
had higher concentrations of serum monoclonal protein (Wilcoxon
P = .07).
Aneuploidy correlation We compared the percentage of abnormal cells with13 versus
those with aneuploidy (Table 4).
Heterogeneity was common for both abnormalities, although in general
13 had a greater tendency to involve a large fraction of the clonal
cells. Among all patients with translocations, a significant proportion
of them did have the abnormality detected in less than 50% of clonal
PCs: 9 (38%) of 24 with an VH/CH
translocation, 3 (20%) of 15 with t(11;14)(q13;q32), 1 of 5 with
t(4;14)(p16.3;q32), and 1 of 3 with t(14;16)(q32;q23). In 15 patients,
we attempted to correlate the proportion of PCs with aneuploidy with
the percentage of PCs with an Ig translocation (IgH, specific partners,
or IgL-). In several patients the percentage of abnormal PCs with
aneuploidy was higher than the abnormal PCs with a translocation or
with 13.
Cyclin D1 and FGFR3 detection We tested for FGFR3 up-regulation by immunofluorescence in 3 patients using leftover slides and found a 1:1 correlation with t(4;14)(p16.3;q32) (Figure 2). We also found that cyclin D1-positive nuclear staining could only be demonstrated in patients with t(11;14)(q13;q32). Eight (57%) of 14 patients with t(11;14) (q13;q32) had cyclin D1-positive staining in the cell nucleus. In contrast, none of the 6 patients without t(11;14)(q13;q32) had cyclin D1-positive staining.
Our findings support the hypothesis that translocations involving Ig loci, including t(4;14)(p16.3;q32) and t(14;16)(q32;q23), represent early cytogenetic events in PC dyscrasias and are likely of pathogenetic importance.7,8 All translocations observed in MM are also seen in MGUS We have been able to identify the chromosomal partner regions for IgH translocations in 21 (77%) of 27 patients, leaving only about one fourth of patients with suspected various partners. Our results now also show that translocations involving the IgL- locus
also occur in 11% of patients with MGUS. However, and in contrast to
the results of Avet-Loiseau and colleagues,12 we observed
t(4;14)(p16.3;q32) and t(14;16)(q32;q23) in 9% and 5% of patients
with MGUS, respectively, which is a similar prevalence we have found
for these translocations in patients with MM (R.F., unpublished
observations, June 2002, and Fonseca et al36).
Our ability to detect t(4;14)(p16.3;q32) or t(14;16)(q32;q23) in MGUS may be related to the sets of probes, which bracket all reported human MM cell line breakpoints in these partner chromosomal regions, we used in this study. For instance, we used a pool of probes instead of a single clone because we have observed deletions surrounding the translocation breakpoints in 16q23 translocations in human MM cell lines with t(14;16)(q32;q23) (R.F., unpublished data, May 2002) and, thus, probe signals may be lost as a consequence of translocation events resulting in false-negative results. In many cases we have found a pattern consistent with loss of a derivative chromosome when studying t(4;14)(p16.3;q32) in MM samples resulting in only 1 fusion signal. In our MGUS series we found a high concordance between the percentage of PCs with abnormal signal patterns by both the fusion and IgH break-apart strategy in individual patients (Table 1). Alternatively, there may be differences in the referral patterns or populations that are being studied that account for these variations. Progression to MM The relative short follow-up time of patients in our study prevents us from estimating the predictive capacity of evolution to MM of specific Ig translocations in MGUS. The long period of stability after diagnosis (and translocation detection) in patients with t(4;14)(p16.3;q32) or t(14;16)(q32;q23) suggests that, much like the t(11;14)(q13;q32), these abnormalities alone, at least in some cases, are not sufficient for progression from MGUS to MM and are likely primary events for disease pathogenesis. It is, however, possible that time of evolution of these patients may be shorter than for patients without the abnormality. Compared with other studies,37 we observed a higher prevalence of t(11;14)(q13;q32) in MGUS than in MM38,39 and more recently have also found a high incidence of this same abnormality in the clonal PCs of AL patients.13 If these data are correct, it may suggest t(11;14)(q13;q32) is negatively selected for progression from an early-state PC disorder to MM. This hypothesis can be tested through longitudinal studies of MGUS patients.Chromosome 13 abnormalities The prevalence of13 among the patients in the present study
was approximately 50% and is similar to that reported in
MM.19,21,31 Other investigators have reported 13 in
15% to 50% of patients with MGUS.19,20 Most studies
indicate that when a chromosome abnormality is detected in MM, it
occurs in most clonal PCs,31,35 and this is consistent
with our findings in MGUS, although other reports show greater
heterogeneity in MGUS.35 These observations suggest that
for many patients the acquisition of 13 is not critical for
evolution from MGUS to MM. Patients with t(11;14)(q13;q32) and MGUS
appear to be approximately equally likely to have 13 (about 50%) as
patients with MM and t(11;14)(q13;q32) (54%).38 In
contrast, we recently observed a strong association between 13 and
t(4;14)(p16.3;q32) since the early stages of PC
disorders.36 We have found 13 in more than 85% of
patients with MM and the t(4;14)(p16.3;q32) and have also found it in 3 of 4 patients with MGUS,36 but this observation needs to
be confirmed in a larger cohort of patients. Our sample size is too
small to infer much about the association of t(14;16)(q32;q23) and
13. The results presented here are in disagreement with several of
the published series and would suggest that 13 is not necessarily
important in the progression from MGUS to MM, but this issue is clearly in need of further study.
Percentage of abnormal cells and relation to prevalence This study shows that in most MGUS patients, and like has been reported by Avet-Loiseau et al,12 chromosome abnormalities are seen in most of the clonal cells. Clonal cells were defined in their study by virtue of aneuploidy, while we estimated the actual number of clonal cells by virtue of the light-chain cytoplasmic stain ( or ) restriction.12 In most
cases tested we found a chromosomal abnormality, including
translocations, ploidy, or 13, in most of the
light-chain-restricted cells. However, and like in Avet-Loiseau's
study,12 we also found patients where translocations
involved a smaller percentage of light-chain-restricted clonal cells.
Although it is possible that not all light-chain-restricted PCs form
part of the clone (some polyclonal PCs with the same light chain usage
"contaminate" the scoring), their contribution is likely minimal.
It is also possible that translocations do not involve most clonal PCs,
because they may occur early in the process of disease pathogenesis
(MGUS) but may not be the first events. Because of this, and the
observation that several more patients had a low proportion of PCs with
abnormal fusions (equivocal results), we may be underestimating the
actual incidence of Ig translocations in MGUS.
Aneuploidy versus structural chromosomal abnormalities It is unknown in the PC disorders which genetic lesion occurs first in the clonal PCs of patients with MGUS: aneuploidy or translocations. Because of the ubiquitous nature of aneuploidy, the high prevalence of IgH translocations in MGUS, and the lack of a clearly defined precursor to MGUS, this question remains unsolved. The results of our study make us speculate that in some cases aneuploidy may occur before IgH translocations. This would be consistent with a model where genomic instability occurs first, results in aneuploidy, and is the permissive event for structural and numeric chromosomal abnormalities to occur.12,40,41 In MGUS, and in contrast to MM, IgH and IgL- translocations frequently occur in less than
75% of PCs. In this study we encountered several patients (Table 4)
where the percentage of aneuploid PCs (by centromeric probes or 13
assay) was greater than the percentage of PCs with any given
translocations. In many patients the differences between the percentage
of abnormal cells by a ploidy assay and translocation percentage
abnormal cells were modest (perhaps technical), but in some the
absolute percentage difference exceeded 35 points (likely real). Even
when larger numbers of patients need to be studied, our results would
suggest that aneuploidy arises at the time or just before IgH
translocations occur.
Comparison with other series of patients While our series shows similarities with that published by Avet-Loiseau and colleagues,12 several differences are notorious and will need to be further clarified in future studies. Some of these differences are of modest percentage difference but may have important implications for the interpretation of our results. The major differences between both series of patients include that we can detect the 3 main partner chromosomes to IgH translocations (11q13, 4p16.3, and 16q23) in 77% of cases while they have been able to identify these same chromosomal partners in only 37% of IgH translocations. In many cases we have found that clonal chromosomal abnormalities, but particularly IgH translocations, may involve only a fraction of the light-chain-restricted cells. We also found a significantly higher incidence of13 (about 50%), and lastly we found that when the
abnormality is detected it is present in most clonal PCs.
Oncogene up-regulation Because of the oncogenic potential of FGFR334 and cyclin D1,42 we examined clonal PCs in MGUS (a low proliferative index clonal state) for their genetic up-regulation. Using the technique published by Chesi et al,34 we confirmed up-regulation of FGFR3 by the t(4;14)(p16.3;q32) in MGUS, which further supports our finding of these abnormalities in the early stages of the PC disorders.34,43 We also used immunohistochemical detection of cyclin D1 by a method recently described by us.33 While nuclear positivity was seen only in cases with the t(11;14)(q13;q32), the test was positive in only 8 (57%) of 14 patients, and in other patients the staining was difficult to interpret due to the low percentage of clonal PCs present in the BM biopsy.44MGUS/SMM clonal cells can have more than one translocation In MGUS and SMM the clonal cells can have 2 coexistent Ig translocations, each with its putative dysregulation of oncogenes. In this series of patients we detected 3 patients with 2 translocations. While it is possible that separate clonal populations have different translocations, in 2 of 3 patients the clonal PCs shared 2 translocations in the same PC; the aggregate percentage exceeded 100 (199% and 121%). This has been previously detected in other studies, although these appear to be rare.17,18 However, we recently finished a large cIg-FISH study of IgH translocations in MM36,38 but could not find 2 coexistent translocations in the clonal PCs of MM, and others have made similar observations.10,39 This issue may be better addressed through a detailed metaphase-FISH16 or spectral karyotype (SKY)17,18 study.Importance Preliminary observations suggest a biologic uniqueness to groups of MM defined by the specific cytogenetic markers, as detected by cIg-FISH. We recently reported that patients with the t(11;14)(q13;q32), as detected by FISH, appear to have specific biologic features and better survival than patients without the abnormality.38 These observations further validate that Ig translocations are likely important in the pathogenesis of the PC disorders and may be seen as candidates for therapeutic interventions aimed at the consequences of oncogene up-regulation.
Submitted August 17, 2001; accepted April 3, 2002.
Supported by the Multiple Myeloma Research Foundation and the Mayo Foundation. R.F. and S.V.R. are Leukemia and Lymphoma Society Translational Research Awardees. R.F. is supported by the CI-5 Cancer Research Fund-Lilly Clinical Investigator Award of the Damon Runyon-Walter Winchell Foundation. This work is also supported in part by Public Health Service grant R01 CA83724-01 from the National Cancer Institute (R.F.) and grant P01 CA62242 (R.A.K., J.A.L., G.J.A., P.R.G.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Rafael Fonseca, Division of Hematology and Internal Medicine, Stabile 6-28, Rochester, MN 55905; e-mail: fonseca.rafael{at}mayo.edu.
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R. A. Kyle, T. M. Therneau, S. V. Rajkumar, E. D. Remstein, J. R. Offord, D. R. Larson, M. F. Plevak, and L. J. Melton III Long-term follow-up of IgM monoclonal gammopathy of undetermined significance Blood, November 15, 2003; 102(10): 3759 - 3764. [Abstract] [Full Text] [PDF]
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R. Fonseca, C. S. Debes-Marun, E. B. Picken, G. W. Dewald, S. C. Bryant, J. M. Winkler, E. Blood, M. M. Oken, R. Santana-Davila, N. Gonzalez-Paz, et al. The recurrent IgH translocations are highly associated with nonhyperdiploid variant multiple myeloma Blood, October 1, 2003; 102(7): 2562 - 2567. [Abstract] [Full Text] [PDF]
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M. V. Dhodapkar, M. D. Geller, D. H. Chang, K. Shimizu, S.-I. Fujii, K. M. Dhodapkar, and J. Krasovsky A Reversible Defect in Natural Killer T Cell Function Characterizes the Progression of Premalignant to Malignant Multiple Myeloma J. Exp. Med., June 16, 2003; 197(12): 1667 - 1676. [Abstract] [Full Text] [PDF]
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R. Fonseca, E. Blood, M. Rue, D. Harrington, M. M. Oken, R. A. Kyle, G. W. Dewald, B. Van Ness, S. A. Van Wier, K. J. Henderson, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma Blood, June 1, 2003; 101(11): 4569 - 4575. [Abstract] [Full Text] [PDF]
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M. Santra, F. Zhan, E. Tian, B. Barlogie, and J. Shaughnessy Jr A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript Blood, March 15, 2003; 101(6): 2374 - 2376. [Abstract] [Full Text] [PDF]
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G. R. Boersma-Vreugdenhil, T. Peeters, and B. J. E. G. Bast Translocation of the IgH locus is nearly ubiquitous in multiple myeloma as detected by immuno-FISH Blood, February 15, 2003; 101(4): 1653 - 1653. [Full Text] [PDF]
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J. J. Keats, T. Reiman, C. A. Maxwell, B. J. Taylor, L. M. Larratt, M. J. Mant, A. R. Belch, and L. M. Pilarski In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression Blood, February 15, 2003; 101(4): 1520 - 1529. [Abstract] [Full Text] [PDF]
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S. Barille-Nion, B. Barlogie, R. Bataille, P. L. Bergsagel, J. Epstein, R. G. Fenton, J. Jacobson, W. M. Kuehl, J. Shaughnessy, and G. Tricot Advances in Biology and Therapy of Multiple Myeloma Hematology, January 1, 2003; 2003(1): 248 - 278. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
after 20 to 35 years of follow-up.
Mayo Clin Proc.
1993;68:26-36