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NEOPLASIA
From the Hematology Laboratory, INSERM U463, and the
Department of Clinical Hematology, University Hospital, Nantes, France.
Rearrangements of the c-myc oncogene have
been found in most plasmacytomas induced in mice and human myeloma cell
lines (HMCLs) analyzed so far. However, neither induced mouse
plasmacytomas nor HMCLs represent relevant models for human multiple
myeloma (MM). To evaluate the incidence of c-myc
rearrangements in human plasma cell dyscrasias, sets of probes were
generated to allow direct assessment of c-myc
translocations on interphase plasma cells by using fluorescence in situ
hybridization. After validation of these probes, a large cohort of
patients with either newly diagnosed MM (n = 529), relapsed MM
(n = 58), primary plasma cell leukemia (PCL; n = 23), monoclonal
gammopathy of undetermined significance (n = 65), or smoldering MM
(n = 24) were analyzed. C-myc rearrangements were
identified in 15% of patients with MM or primary PCL, independently of
the stage of the disease (ie, diagnosis or relapse and MM or
primary PCL). Analysis of the 2 main translocations observed on
karyotyping, ie, t(8;14) and t(8;22), revealed that these specific
translocations represented only 25% (23 of 91) of c-myc
rearrangements. c-myc rearrangements were then correlated
with several other patients' characteristics: illegitimate
IgH recombinations, chromosome 13 deletions, and serum
C-myc rearrangement, especially
through chromosomal translocation t(12;15), is a major event in the
oncogenesis of plasmacytomas induced in mice.1 This
translocation juxtaposes the c-myc proto-oncogene and the
gene encoding the immunoglobulin heavy chain (IgH). The main
molecular consequence of this translocation is nonregulated c-myc expression throughout the cell cycle, leading to
cellular proliferation. This specific chromosomal rearrangement is
observed consistently in several models of induced mouse plasmacytomas. In the model of pristane-induced plasmacytomas, 100% of tumors bear a
rearranged form of c-myc.2 In the
Eµ-IL6 transgenic model, BALB/c mice develop
plasmacytoma with t(12;15).3 Similarly, most transgenic
mice bearing a Eµ-v-abl transgene will develop plasmacytomas, with 80% of them showing rearrangements of
c-myc.4 Finally, even in the
Eµ-bcl2 transgenic model, two thirds of the plasmacytomas in the mice bear an Ig-c-myc
rearrangement.5
The only mouse model lacking recurrent c-myc activation is
the 5T model, which consists of a plasmacytoma occurring spontaneously in 0.5% of C57BL/KW mice.6 This model has been recognized
as the most relevant to human multiple myeloma (MM). In MM, cytogenetic studies are much less productive (only 30%-50% of informative cases
with use of conventional cytogenetics) and have so far failed to
identify any specific rearrangement in 100% of cases. C-myc rearrangements have been observed in some cases of MM. Most of these
rearrangements are t(8;14), the human equivalent of the mouse t(12;15).
Variant translocations involving the IgL An evaluation of c-myc rearrangements in human myeloma cell
lines (HMCLs) highlighted this locus as a hot spot of chromosomal rearrangements, even in human MM. Using an approach based on
fluorescence in situ hybridization (FISH), Shou et al10
showed that 18 of 20 HMCLs had an 8q24 rearrangement and that another
one had a rearrangement involving L-myc. Thus, using
specifically dedicated probes, Shou et al10 showed that
complex rearrangements involving c-myc, IgH,
IgL Patients
Twenty-two HMCLs available in our laboratory were also analyzed. Eleven
were established by us (XG-1,12 XG-2,12
XG-5,12 XG-6,12 XG-7,12 SBN-1,
MDN, BCN, NAN-1, NAN-2, and NAN-3), and 11 were obtained from other
laboratories (LP-1,13 SKMM-1,14 OPM-2,15 JJN3,16 Karpas 620,17
RPMI 8226,18 L363,19 U266,20
AMO-1,21 EJM,22 and ANBL-623).
All the 11 HMCLs established in our laboratory and analyzed in this
study correspond to early passages of the HMCL. Moreover, results were
compared with those obtained in patients from whom the HMCL was derived (SBN-1, MDN, BCN, NAN-1, NAN-2, and NAN-3)
FISH experiments
We selected 22 yeast artificial chromosome (YAC) probes according to their location in the 8q24 region in the Centre d'Etude du Polymorphisme Humain database (www.cephb.fr). After labeling with Spectrum Orange-deoxyuridine triphosphate (dUTP; Vysis, Voisins-le-Bretonneux, France) or Spectrum Green-dUTP (Vysis), these probes were tested in 22 patients with Burkitt lymphoma (chimeric YAC probes were discarded). Fifteen patients had t(8;14), 5 had t(8;22), and 2 had t(2;8). Analysis of metaphases allowed classification of the probes as either c-myc centromeric (c-myc-C) probes, ie, those that hybridized on the der(8), or c-myc telomeric (c-myc-T) probes, ie, those that were translocated on one of the partner derivative chromosomes. After this probe selection, we conducted dual-color FISH experiments, combining each c-myc-C probe (labeled in green) with each c-myc-T probe (labeled in orange) on peripheral blood mononuclear cells from 5 healthy volunteers and bone marrow cells from 5 healthy donors to select the better set of probes. Criteria for the selection were good signal quality and the smallest gap between the 2 signals. Because of the dispersion of the breakpoints, probes selected for this analysis were necessarily far away from each other and thus may not show a fusion signal in each interphase cell. After this selection, we determined the cut-off level for positivity, ie, the threshold of probe separation enabling assessment of a c-myc rearrangement. Our criterion for fusion (ie, nonrearranged configuration) was a distance between the 2 probes smaller than the size of a signal. The cut-off value was then fixed at the mean ± 3 SDs. To characterize c-myc rearrangements further, we designed 2 sets of probes enabling direct assessment of t(8;14) and t(8;22) on
interphase plasma cells. Translocation t(8;14) was assessed by a fusion
between a green-labeled IgH-specific cosmid probe (Ig10,
mapping at the centromeric border of the IgH
gene11) and an orange-labeled c-myc-specific
YAC probe (934E1, encompassing the c-myc
locus).24 For translocation t(8;22), we used the
same c-myc-specific probe with an orange-labeled P-1
artificial chromosome (PAC) probe specific for IgL Finally, patients were analyzed for illegitimate IgH
rearrangements, especially for the 3 most frequent specific 14q32
translocations Translocation t(11;14) was identified by using the Ig10 cosmid probe (labeled in green) and the cos 6.22 probe (labeled in orange; provided by Ed Schuuring, Department of Pathology, Leiden, The Netherlands), mapping at 11q13 and containing the CCND1 gene.25 To test this probe, 50 patients with MM and t(11;14) previously diagnosed with a commercial probe (Vysis) were reanalyzed with this set of probes. All 50 patients were also positive for t(11;14) on analysis with this probe set. The analysis of 2000 peripheral blood or bone marrow cells from healthy volunteers enabled fixation of the positivity threshold at 10.5% (mean ± 3 SDs). Translocation t(14;16) was analyzed by using the Ig10 cosmid probe (labeled in green), and a c-maf-specific PAC probe (labeled in orange; provided by Leif Bergsagel, Department of Pathology, Cornell University).26 This probe is localized on the telomeric side of all the 16q23 breakpoints of the t(14;16) reported so far.26,27 Moreover, to test the ability of this set of probes to detect t(14;16), we blindly analyzed 4 HMCLs (JJN3, ANBL-6, BCN, and NAN-2) and 4 patients with cytogenetically proven t(14;16). In all 8 cases, IgH-c-maf fusions were observed in interphase plasma cells. The cut-off value for positivity was fixed at 9.8% (mean ± 3 SDs). For all probes, at least 100 nuclei/patient were counted.
C-myc rearrangements are accurately detected by interphase FISH Thirteen of the 22 YAC clones were nonchimeric and localized at 8q24. Six mapped at the centromeric side of 8q24 breakpoints and 7 at the telomeric side. These 13 YAC probes were analyzed (each centromeric clone combined to each telomeric clone) on normal peripheral blood and bone marrow cells to select the set of probes with the lowest false-positive cut-off level. The 861F11 and 932H6 clones yielded the best results and were chosen for the c-myc analysis (Figure 1). Two thousand cells were analyzed by 2 observers, and a separation of the 2 probes was observed in 6.7% ± 1.17%. The cut-off value was fixed at 11% (mean ± 3 SDs). We then reanalyzed the 22 specimens from patients with Burkitt lymphoma with this set of probes and showed that they accurately detected the c-myc translocations in all cases.
The analysis of sets of probes specific for IgH-c-myc and
IgL C-myc rearrangements are present in 15% of primary MM tumors and more than half of HMCLs We first screened the 699 specimens from patients for c-myc rearrangements by using the c-myc-C and c-myc-T set of probes (Figure 1C). A rearrangement was observed in 79 of 529 patients with newly diagnosed MM (15%), 5 of 58 patients with relapsed MM (9%), 3 of 23 patients with primary PCL (13%), 2 of 65 patients with MGUS (3%), and 1 of 24 patients with SMM (4%) (Table 1). The median percentage of plasma cells showing the c-myc rearrangement was 62% (range, 19%-100%). Interestingly, one patient with newly diagnosed MM had a high-level amplification of the c-myc locus, with both probes present in approximately 20 to 40 copies, without rearrangement. The analysis of the 22 HMCLs showed a significantly higher incidence of c-myc rearrangements, which were observed in 10 of 22 HMCLs (45%; P = .0001 for difference from samples from patients with overt MM and primary PCL). The incidence of c-myc rearrangements was lower in our HMCLs (4 of 11 versus 8 of 11 for others), but the difference was not significant. There was complete concordance between the presence (or absence) of c-myc rearrangements in the original patients and the HMCLs (SBN-1, BCN, MDN, NAN-1, NAN-2, and NAN-3).
We then reanalyzed all 699 patients and 22 HMCLs by using the
t(8;14)-specific and t(8;22)-specific sets of probes. Fusions between
IgH and c-myc sequences were observed in 15 patients (13 with newly diagnosed MM and 2 with relapsed MM; Table 1)
and in 7 HMCLs (LP-1, SKMM-1, OPM-2, JJN3, Karpas 620, AMO-1, and XG-5), whereas c-myc-IgL Therefore, including these cases with insertions, c-myc rearrangements were observed in 82 of 529 patients with newly diagnosed MM (16%), 6 of 58 patients with relapsed MM (10%), and 12 of 22 HMCLs (55%). C-myc rearrangements do not correlate with other
chromosomal changes but are significantly associated with high serum
levels of  2-microglobulin were analyzed in all patients with
MM or primary PCL at diagnosis to classify patients according to a
cut-off value of 3 mg/L. Results are shown in Table 2. C-myc rearrangements were
observed in 13 of 119 patients without illegitimate IgH
rearrangement (11%; not significant [NS]), 14 of 60 patients with
t(4;14) (23%; P = .08 for difference from other
patients), 17 of 115 patients with t(11;14) (15%; NS), 2 of 14 patients with t(14;16) (14%; NS), and 45 of 302 patients with
illegitimate IgH rearrangements involving unknown partners (15%; NS). Analysis of chromosome 13 status (deleted or not) did not
reveal any significant correlation with c-myc
rearrangements. The only significant correlation was with serum
2-microglobulin levels. C-myc rearrangements were
observed significantly more often in patients with 2-microglobulin
levels above 3 mg/L (62 of 323 patients versus 29 of 287;
P = .002).
Rearrangements of the c-myc locus have been
observed in most plasmacytomas induced in mice, regardless of the model
of generation (transgenic models with several oncogenes or
pristane-induced plasmacytomas1), but not in the
spontaneous 5T model in C57Bl mice. Shou et al10 reported a
high incidence (90%) of such rearrangements in HMCLs. Comparisons
between the nature of c-myc rearrangements in the 2 models
reveal important similarities. In animal models, c-myc
rearrangements involved the IgH locus, through t(12;15) translocations. In HMCLs, most (15 of 18) rearrangements involved the
IgH locus, through a large number of different molecular
recombinations. Classic t(8;14) was observed in 5 cases, whereas other
rearrangements involved insertions of sequences specific for one or the
other gene within the other locus. In 2 cases, the insertional events involved c-myc and IgL However, some data reported by Shou et al10 suggest
that these rearrangements might appear late in the natural history of human MM and are secondary rather than primary oncogenetic events. These data prompted us to analyze primary human MM tumors to determine the place of c-myc in MM oncogenesis. The first step was to
generate a set of probes enabling detection of all the c-myc
rearrangements on interphase plasma cells. Because some of the
c-myc rearrangements occurred through insertional events (as
shown by Shou et al10), our set of probes would miss these
rearrangements. Moreover, some rearrangements occurred through
insertion of IgL Our results were different from those obtained in either plasmacytomas
induced in mice or HMCLs. First, the incidence of c-myc rearrangements in patients with plasma cell malignant disease was
somewhat lower (15%) than that observed in the 14 patients analyzed by
Shou et al (7 of 14).10 Second, whereas most
c-myc rearrangements described in the models involved
IgH or IgL Analysis of our large cohort of patients showed that c-myc rearrangements are likely to occur as soon as diagnosis, since the incidence was not higher in patients analyzed at relapse of MM than in those with newly diagnosed MM (16% versus 10%). Moreover, we observed c-myc rearrangements in 2 of 65 and 1 of 24 patients with MGUS and SMM, respectively. However, a more detailed analysis revealed a wide patient-to-patient range in the percentage of plasma cells with the rearrangement (19%-100%). This finding favors the hypothesis that c-myc rearrangements are secondary events, thereby supporting the results of Shou et al,10 who detected c-myc rearrangements only in subsets of clonal metaphase plasma cells. Furthermore, in our current study, most c-myc rearrangements occurred through translocation involving nonimmunoglobulin genes (68 of 91 [75%]). Classic translocations, ie, t(8;14) and t(8;22), were observed in 15 and 8 cases, respectively. Because cytogenetic analyses were not routinely performed in our series, the nature of the chromosomal partner in the other 68 patients is largely unknown. Only 2 patients (both with primary PCL) underwent successful cytogenetic analysis, one with a t(6;8)(q15;q24) and one with a t(8;13)(q24;q14).28 In both cases, metaphase and interphase FISH accurately detected the abnormality, thereby showing involvement of the c-myc locus. We also found a novel recurrent translocation, ie, t(6;8)(q15;q24), in 2 patients with primary PCL.28 In an update of their multicolor FISH analysis, Sawyer et al29 described several translocations involving 8q24 and another partner, such as 16q22, 1p13, and 6q21. Thus, many partners seem to be involved in c-myc deregulation, even though t(8;14) and t(8;22) appear to occur most frequently in cytogenetic analyses. The discrepancy between the incidence of c-myc in our series and the series reported by Shou et al10 has no clear explanation. A possible reason for the disparity is the difference between the probes used in the 2 studies. However, we did detect c-myc rearrangements in the 8 HMCLs that were also analyzed by Shou et al.10 Another possible explanation is that c-myc rearrangements are acquired during HMCL evolution. Most of the HMCLs established in our laboratory have been established only recently or, in the case of the XG HMCL, correspond to early passages. Moreover, we analyzed 6 primary patient/derived HMCL pairs and found a complete agreement in results (2 with and 4 without c-myc rearrangement). In contrast, most of the HMCLs obtained from other laboratories were established several years ago and may have acquired their c-myc rearrangements. We compared the c-myc configuration with other
characteristics in patients with either MM or primary PCL, including
illegitimate IgH rearrangements, chromosome 13 deletion, and
serum In conclusion, our data do not confirm those obtained in HMCLs and plasmacytomas induced in mice. However, most of the murine models are not good reproductions of the human disease, and many biologic findings in mouse plasmacytomas are not relevant for human MM. The most relevant model of human MM is the spontaneous 5T model, in which c-myc rearrangements are rarely reported. The data presented here provide additional support for use of this model in future animal studies.
We thank Axelle Daviet, Stéphanie Saulnier, and Hélène Masson for excellent technical assistance.
Submitted April 16, 2001; accepted July 9, 2001.
Supported by grants from the Association de Recherche contre le Cancer and the Fondation de France.
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: Hervé Avet-Loiseau or Régis Bataille, Laboratoire d'Hématologie, Institut de Biologie, 9 quai Moncousu, 44093 Nantes Cedex 01, France; e-mail: havetloiseau{at}chu-nantes.fr or frb{at}sante.univ-nantes.fr.
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Top
Abstract
Introduction
locus have also
been reported. However, in contrast to results in mouse models, both
these translocations occur in less than 10% of patients with
MM.
t(11;14), t(4;14), and t(14;16)
2 and C
constant genes
(labeled in green) and the yIgH6-9 cosmid (labeled in orange; provided
by Michael Kuehl, National Cancer Institute, Bethesda, MD). The latter
probe hybridized to the more telomeric VH
genes.
light chains.
Leukemia.
1989;3:729-735