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Molecular Oncology, Markers, Clinical Correlates |
1 Academic Unit of Haematology and Oncology, University of Leeds, Leeds, United Kingdom; 2 Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts; 3 Jerome Lipper Multiple Myeloma Center; Dana-Farber Cancer Institute, Boston, Massachusetts; and 4 Royal Marsden Hospital, Surrey, United Kingdom
ABSTRACT
Purpose: Our purpose in this report was to define genes and pathways dysregulated as a consequence of the t(4;14) in myeloma, and to gain insight into the downstream functional effects that may explain the different prognosis of this subgroup.
Experimental Design: Fibroblast growth factor receptor 3 (FGFR3) overexpression, the presence of immunoglobulin heavy chain-multiple myeloma SET domain (IgH-MMSET) fusion products and the identification of t(4;14) breakpoints were determined in a series of myeloma cases. Differentially expressed genes were identified between cases with (n = 5) and without (n = 24) a t(4;14) by using global gene expression analysis.
Results: Cases with a t(4;14) have a distinct expression pattern compared with other cases of myeloma. A total of 127 genes were identified as being differentially expressed including MMSET and cyclin D2, which have been previously reported as being associated with this translocation. Other important functional classes of genes include cell signaling, apoptosis and related genes, oncogenes, chromatin structure, and DNA repair genes. Interestingly, 25% of myeloma cases lacking evidence of this translocation had up-regulation of the MMSET transcript to the same level as cases with a translocation.
Conclusions: t(4;14) cases form a distinct subgroup of myeloma cases with a unique gene signature that may account for their poor prognosis. A number of non-t(4;14) cases also express MMSET consistent with this gene playing a role in myeloma pathogenesis.
INTRODUCTION
The t(4;14) is seen in 
10–20% of presenting cases of multiple myeloma and has been suggested to be associated with a poor prognosis (1, 2, 3, 4)
. The molecular events leading to the translocation have been extensively studied and are thought to be due to aberrant immunoglobulin class switching recombination (5, 6, 7, 8, 9, 10)
. As a consequence of the rearrangement, there is a reciprocal translocation of genetic material between the immunoglobulin heavy chain region (IgH) on chromosome 14q32 and the 5' region of MMSET on chromosome 4p16.3. This leads to at least two genes, fibroblast growth factor receptor 3 (FGFR3) on the der(14) and multiple myeloma with a SET domain (MMSET) on the der(4), being brought under the influence of the strong immunoglobulin gene enhancers E
and Eµ respectively. The molecular characterization of cell lines known to carry the t(4;14) have identified the consistent up-regulation of FGFR3 expression and the formation of a novel hybrid RNA fusion product consisting of upstream immunoglobulin sequences fused to the downstream sequences of MMSET (IgH-MMSET).
These cell line observations have been extended into patient material in which we and others have demonstrated that FGFR3 is overexpressed in the majority of cases carrying a t(4;14) translocation (9 , 11) . However, although an IgH-MMSET hybrid transcript can be detected in all cases with FGFR3 overexpression, the reverse is not consistently so (12) . Cases have been identified where IgH/MMSET hybrid transcripts are present but FGFR3 overexpression is lacking because of an interstitial deletion within FGFR3. This has lead to the suggestion that, although FGFR3 deregulation may be critical for the early stages of myeloma pathogenesis, dependence on it may be lost later in the disease course.
In contrast to FGFR3, the deregulation of MMSET seems to be a universal feature of cases carrying a t(4;14). The site of the breakpoints on chromosome 4 have been well described, and the location of these breaks suggest that cases with a t(4;14) can be further subdivided according to the variant of MMSET they express. Studies of the coding sequence have identified two initiation sites located in exon 3 and exon 15, leading to the production of three possible transcripts (7) . Transcripts initiated from exon 3 are polyadenylated in either exon 11 (type I), or exon 24 (type II) as a result of alternative splicing occurring from exon 10 to 11, or exon 10 to 12. A further possible transcript, type III (IREII-BP), may also be produced by initiation from exon 15. Breakpoints in exon 2 are able to produce three possible transcripts (type I 647 aa, type II 1365 aa, and type III 584 aa), whereas breaks in or after exon 3 can only produce one transcript (type III 584 aa).
To investigate the consequences of the t(4;14), we chose to use a global expression microarray approach to look at the pattern of genes expressed in plasma cells isolated from cases of myeloma that constitutively express FGFR3, compared with cases of myeloma that do not. The aim being to discover genes and pathways dysregulated as a consequence of the t(4;14) and to gain insight into the downstream functional effects occurring in these cells that differentiate them from other cases of myeloma and that could explain the different prognosis of this subgroup.
MATERIALS AND METHODS
Samples and Plasma Cell Selection.
Bone marrow aspirate samples were obtained after informed consent from 29 myeloma patients. After 0.86% ammonium chloride red cell lysis, plasma cells were positively selected by using CD138 microbeads and Magnet Assisted Cell Sorting (Miltenyi Biotech, Bergisch Gladbach, Germany), according to the manufacturer’s instructions. The final purity of these cells (>95%) was assessed by morphology and flow cytometry (FACSort BD Biosciences, San Jose, CA).
Detection of the t(4;14) by Reverse Transcription-PCR and Characterization of IgH/MMSET Breakpoints.
Patients with t(4;14) translocations were identified by a combination of two reverse transcription-polymerase chain reaction (RT-PCR) assays as described previously (9)
. The first approach used PCR to detect the IgH-MMSET fusion product, with primers that span the breakpoint (13)
, and the second demonstrated overexpression of the FGFR3 transcript, which is only seen in the presence of a translocation (9)
. cDNA was prepared by using the Superscript reverse transcriptase enzyme (Invitrogen Life Technologies, Inc. Paisley, United Kingdom) with random hexamer primers. PCR primer sequences are reported elsewhere (9
, 13)
. Both PCR assays used LA Taq polymerase (Takara Bio Inc., Shiga, Japan) and the following thermal cycling conditions: 95°C for 3 minutes; 35 cycles of 95°C for 30 seconds, 60°C for 45 seconds, and 72°C for 45 seconds; ending at 72°C for 5 minutes. For sequencing, DNA bands were separated with 1.5% agarose gel electrophoresis and were stained with ethidium bromide. PCR products were excised and cleaned by using the QIAquick gel purification system (Qiagen, Crawley, UK) according to the manufacturer’s instructions. DNA bands were sequenced in both directions by using PCR primers. Approximately 100 ng of purified DNA were used in the sequencing reaction (Big Dye Terminator kit; PE Biosystems, Warrington, United Kingdom); and the sequences were analyzed with sequence analysis software (Applied Biosystems, Warrington, UK).
Gene Array.
RNA was extracted by using commercially available kits (Qiagen and Stratagene, La Jolla, CA), according to manufacturers’ instructions, and was amplified with a modified SMART PCR protocol (BD Biosciences, Palo Alto, CA), in which a 5' T7 polymerase promoter site was incorporated to create amplified cDNA compatible with downstream processing for the Affymetrix GeneChip system (14)
. Human Genome U95Av2 GeneChip arrays (Affymetrix, Santa Clara, CA) containing probes for 12,600 expressed sequences, were used for mRNA expression profiling, as described previously (14)
.
Array Analysis.
Array normalization and expression value calculation was performed by using DNA-Chip Analyzer (dChip; freely available to academic users at www.dchip.org; ref. 15
).5
Invariant set normalization was used to normalize arrays at the probe cell level, and the perfect-match only model-based method (15
, 16)
was used for outlier detection, probe selection, and computing expression values. The 29 myeloma patient chips were run at four different time points, which made it necessary to pre-process the data to minimize the number of genes identified as different due to batch differences. In dChip, an array list file with "standardize separators" was used to separate the chips into their respective batches to generate gene-wise standardized values, which were then exported into a text file. These batch standardized data were then read into dChip using the "Get external data" function. It was then possible to use the "Compare Samples" function to identify genes differentially expressed between myeloma cases with and without a t(4;14) translocation. Cases without a t(4;14) were specified as the baseline group (B), and cases with a t(4;14) the experimental group (E). As a result of the standardization procedure it was not possible to compute traditional fold changes; therefore, the standardized expression values in the E and B groups were used for unpaired two-sample t tests. Hierarchical clustering was performed on the original expression data, using gene lists resulting from "compare samples," and "standardize separators" to handle any batch-specific effects. An unsupervised analysis was also carried out by using the dChip "filter genes" function, for which the variation across samples was as follows: 1.10 < SD/mean < 10.00, and Present call % in the array used was 
20%.
RESULTS
FGFR3 Expression and Splice Variants.
Five cases were identified by PCR as having a t(4;14) because they expressed the IgH-MMSET fusion product together with overexpression of FGFR3. Patients with detectable FGFR3 expressed mRNA for both the FGFR3 IIIb and FGFR3 IIIc isoforms, resulting from alternative splicing in the ligand-binding domain. FGFR3 mutation analysis, looking for the common mutations of these cases, revealed no evidence of mutations. For each case, the location of the IgH-MMSET splice site was identified; the genomic breakpoints were located 5' of these sites (Fig. 1
; ref. 10
). The remaining 24 cases were negative for IgH-MMSET transcripts and FGFR3 overexpression.
|
. Of these genes, 67 were overexpressed in the t(4;14) cases compared with non-t(4;14) cases, and 60 were underexpressed (Fig. 2)
. Importantly, some genes included in this list, e.g., MMSET and cyclin D2, have been previously reported as being associated with the t(4;14) translocation.
|
Molecular Consequences for Genes on Chromosome 4.
The IgH enhancer regions are strong and can act over many kilobases of DNA to affect gene expression, potentially deregulating genes not directly at the site of the translocation. We used the expression data derived from the arrays to look at genes on 4p that could be potentially deregulated by the translocation (Table 1)
. The only gene located directly at the breakpoint to be deregulated was MMSET, which was up-regulated in all of the t(4;14) cases, confirming prior data from cell lines. Two other genes, PHOX2B and ARHH, located on 4p12 and 4p13, respectively, were also significantly different between cases with and without the translocation. However, these genes are located many hundreds of kilobases from the translocation breakpoints and may not be deregulated directly by the translocation. It is important to note that a number of genes located around the breakpoint, including telomeric SPON2 and TACC3 and centromeric LETM1 and TNIP2, are not represented on the Affymetrix U95Av2 chip.
|
. To examine these cases further, we looked at the pattern of hybridization of the individual oligonucleotide sequences representing the MMSET gene arrayed onto the Affymetrix chip. The gene is represented by 16 oligonucleotides that are all situated in the 3' region of the gene in exon 24 (Fig. 4)
. The hybridization pattern seen in cases with a t(4;14) as well as in cases with an increase in MMSET levels in the absence of a translocation was similar and covered the whole of the probe set. This confirmed that the expression changes are real and are not due to the cross-hybridization of a few bad probes.
|
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. For each gene the Human Genome Organization (HUGO) gene nomenclature committee-approved gene name is used, when possible, followed by the abbreviation in parentheses.
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Apoptosis and Related Genes.
A number of genes important in protecting the cell from apoptosis were also identified as being differentially expressed between cases with and without a t(4;14) translocation. Down-regulated genes included Caspase 2 apoptosis-related cysteine protease (CASP2), the active form of which is induced by a variety of apoptotic stimuli, and which a recent report demonstrated is also decreased in mantle cell lymphoma (19)
; Histone deacetylase 1 (HDAC1), which encodes for a component of the histone deacetylase complex, which interacts with retinoblastoma tumor suppressor protein and is a key element in the control of cell proliferation and differentiation; Death effector domain containing gene (DEDD), which regulates programmed cell death and connects with the caspases to mediate formation of the death-inducing signal complex; and Immediate early response gene X-1 (IER3/IEX1) which is regulated by multiple transcription factors including p53, NF-
B/rel, Sp1, and c-Myc and which protects cells from Fas- or tumor necrosis factor type -induced apoptosis.
Membrane Genes.
A number of key adhesion molecules were noted to be up-regulated in the t(4;14) cases. These include N-Cadherin (CDH2), which is both an adhesion molecule and an important downstream target of FGFR3 signaling; Activated leukocyte cell adhesion molecule (ALCAM/CD166), a member of the immunoglobulin superfamily, which mediates both heterophilic (ALCAM-CD6) and homophilic (ALCAM-ALCAM) cell–cell interactions; Vimentin, which has been previously linked with an invasive phenotype of prostate cancer and epithelial carcinomas; Decorin, an important component of the proteoglycan core, which binds type I collagen; and CD43 (leukosialin, sialophorin), which has a prominent role in cell–cell adhesion. We found three differentially expressed chemokine-related genes: CCL18, CCRL2, and CCL13, which were all down-regulated in the cases with a t(4;14), suggesting that there may be differences in distribution of the myeloma plasma cells between the two subsets (t(4;14) versus non-t(4;14)). Differential patterns of cytokine response could mediate differential disease activity and response to therapy; however, we only noted altered levels of two cytokines receptors, IL9R and IL10RA. Both receptors were noted to be down-regulated in t(4;14) cases. Several studies have reported that interleukin (IL)-10 affects myeloma cells by stimulating secondary signals for cell proliferation through oncostatin M (OSM) and IL-11, whereas IL-9 has not, thus far, been implicated in the disease process. The ATP-binding cassette transporter genes are important in mediating membrane transport of a wide range of substances, including drugs across the cell membrane. ABCB1 (previously known as P-glycoprotein/multidrug resistance 1) is well recognized for its ability to mediate resistance to a range of chemotherapeutic drugs. We found this to be underexpressed in t(4;14) plasma cells, which suggests that any drug resistance occurring in these patients is mediated via another mechanism.
Oncogenes.
We found altered expression of a number of oncogenes, including Wilms tumor 1 and B-cell CLL/lymphoma 7B (BCL7B), which are both down-regulated, and v-myb myeloblastosis viral oncogene homolog (avian)-like 1 (MYBL1), which is up-regulated.
Chromatin.
Two genes involved in chromatin structure acetylation/methylation of DNA were differentially expressed between the two groups. Histone 1 H3d, (H1STAH3d) is involved with nucleosome assembly by interacting with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. -Thalassemia/mental retardation syndrome X-linked (RAD54) homolog belongs to SWI/SNF family of chromatin remodeling proteins and is involved in DNA methylation and gene regulation of interphase and chromosomal segregation in mitosis.
DNA Repair Gene Differences.
We found only one DNA repair gene that was differentially expressed between FGFR3-positive and -negative cases. APEX nuclease (apurinic/apyrimidinic endonuclease) 2 (APEX2) is a Class II AP endonuclease that cleaves the phosphodiester DNA backbone 5' to AP sites (sites that occur after DNA damage) and that provides a scaffold support for the activity of a number of subsequent repair processes.
DISCUSSION
Gene array studies performed previously in myeloma have demonstrated that malignant plasma cells can be distinguished from normal plasma cells by their gene expression profiles, and that CD138-selected plasma cells from monoclonal gammopathy of uncertain significance are more similar to their malignant counterparts than to their normal ones (14 , 20, 21, 22) . Furthermore, hierarchical clustering of myeloma cases confirms that myeloma is a heterogeneous disease at the molecular level and that distinct groups of cases can be defined on the basis of the patterns of gene expression (23 , 24) . In the current analysis, we clearly show that cases carrying a t(4;14) can be defined as being different from cases lacking the translocation. The gene signature typical of the t(4;14) cases is limited and equates to 127 genes, 67 of which are up-regulated, whereas the remainder are down-regulated, and contains genes that may explain differences in the biology and outcome of patients with the translocation. Two of the genes highlighted in the supervised analysis were also identified in an unsupervised analysis. The unsupervised analysis used a list comprising genes that varied most across the sample set. The comparison of these two analyses illustrates the fact that there is a core set of genes which are deregulated by the translocation and contribute to the overall heterogeneity of myeloma.
The t(4;14) in multiple myeloma results in a reciprocal translocation between chromosome 14q32 and 4p16.3, repositioning FGFR3 to der(14) and creating a fusion gene with MMSET on der(4) under the influence of strong enhancers from the immunoglobulin heavy chain gene region. FGFR3 is one of a family of five tyrosine kinases through which the fibroblast growth factors signal. These receptors are characterized by an extracellular domain with either two or three immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tyrosine kinase domain. On ligand stimulation FGFR3 undergoes dimerization and tyrosine autophosphorylation, resulting in proliferation and differentiation, depending on the cellular context. FGFR3 is dysregulated by mutations in a number of tumor systems and in inherited conditions associated with abnormal bone growth and development. These mutations are associated with constitutive activation of the tyrosine kinase activity of the gene; however, in myeloma patients such mutations are extremely rare and deregulation seems to occur exclusively as a consequence of the translocation (11 , 25) . The possible oncogenic nature of FGFR3 in myeloma has been examined by a number of groups (26, 27, 28) . These studies demonstrate that FGFR3 is capable of producing lymphoid malignant disease in mice and that overexpression in myeloma cell lines results in increased cell proliferation and survival. Recent studies also suggest that the inhibition of FGFR3 by a small molecule induces differentiation and apoptosis of t(4;14) myeloma cell lines, suggesting that FGFR3 may be a possible therapeutic target (29) .
In contrast to FGFR3, the role of MMSET in myeloma pathogenesis has been more difficult to understand. MMSET is a large gene of 90 kb that comprises 25 exons, is expressed ubiquitously in early development, and undergoes complex alternative splicing. The gene encodes a 136 kDa protein containing four domains: a PWWP domain, an HMG box, a SET domain and a PHD-type zinc finger. A literature and database search identifies nine possible cDNA variants by using the standard criteria of ATG and TATA box on the 5' side to identify initiation sites. Two open reading frames are identifiable: the first in exon 3, translating to produce a full-length isoform of protein (1,365 aa, type II), and four possible truncated variants (647–802 aa, type I), all containing the COOH-terminal hath and HMG domains. A second open reading frame in exon 15 can also produce a hypothetical protein product of 584 aa containing the NH2-terminal hath and SET domains (type III or ILS promoter REII region-binding protein).
We have previously described the sites of the breakpoints on chromosome 4 and can relate these breakpoints to the potential isoforms of MMSET which can be expressed. The probes on the gene chip are located in exon 24, and all cases with a t(4;14) are positive for this area. The primers for the IgH-MMSET PCR are directed to joining gene segment 6 (JH6). In this case series, IgH is joined to MMSET exon 3 in two patients, exon 4 in another two patients, and exon 5 in one patient. This suggests that all of the patients are capable of expressing the 3' sequence and, depending on where the breakpoint is situated with reference to the initiation site in exon 3, may express the 5' sequence. This would result in some patients with a t(4;14) producing the type I, II, and/or III protein, whereas other patients could only produce the type III protein. Twenty-five percent of cases that did not have the IgH-MMSET fusion transcript also expressed the 3' end of the MMSET transcript. Further analysis of these cases is required, but in this initial study, the results suggest that these cases express normal MMSET (type II) or the type III isoform (IREII-BP) only.
The downstream consequences of FGFR3 up-regulation or IgH-MMSET fusion transcripts is unknown; thus, characterizing the differentially expressed genes may help to understand the consequences of abnormal signaling via these pathways in myeloma. Constitutive expression of FGFR3 would be predicted to signal via the RAS/MAPK and JAK/STAT pathway. Genes involved in these pathways were noted to be differentially expressed between cases with and without a translocation. Recent studies have suggested that cyclin expression is important in myeloma pathogenesis, with different myeloma translocation subgroups being characterized by their use of cyclin D1, cyclin D2, or cyclin D3, and the expression of cyclin D2 differentiating our two subgroups would be in keeping with these data (18) . Glycoprotein A repetitions predominant (GARP), a FGF-related gene, was noted to be down-regulated in the t(4;14) cases. It is located in close proximity to cyclin D1 at 11q13–11q14, a gene frequently deregulated by the t(11;14) translocation. In the unsupervised analysis, overexpression of cyclin D1 and cyclin D2 were demonstrated to be mutually exclusive. Data from cyclin D1 transgenic mice and transfection studies demonstrate that overexpression of cyclin D1 is insufficient to cause cell cycle progression alone, and it has been suggested that overexpression of cyclin D1 renders a cell more sensitive to growth-activating signals and/or less sensitive to growth-inhibitory signals (30 , 31) . In this study, although a number of growth-activating and growth-inhibitory genes were highlighted as being altered between cases with and without a translocation, from the literature, no genes appeared to have a direct link with cyclin pathways. A number of genes important in protecting the cell from apoptosis were identified as being differentially expressed between cases with and without a t(4;14) translocation. This suggests that, in addition to the known overexpression of cyclins, which drives entry into the cell cycle, disturbances of pathways associated with apoptosis contribute to the development of B-cell malignant diseases. Of particular interest, death effector domain-containing gene (DEDD) was noted to be down-regulated in cases with the translocation. The death effector domain (DED) is a protein–protein interaction domain shared by adaptors, regulators, and executors of the programmed cell death pathway, and overexpression can induce apoptosis. DED occurs in proteins that regulate programmed cell death, and DED interactions connect with the caspases to mediate formation of the death-inducing signal complex. Accumulating evidence now suggests that DED-containing proteins have additional roles in controlling pathways of cellular activation and proliferation (32) .
Non-homologous end joining (NHEJ) DNA double-strand break (DSB) repair pathways are integral components of class switch recombination, and we postulated that there may be abnormalities in these pathways in myeloma cases with aberrant class switching and translocations involving chromosome 14. Previously, we have reported that two components of the NHEJ pathway, XRCC4 and RAD50, are significantly up-regulated in myeloma cases compared with normal controls, suggesting a role for these DNA repair enzymes in the etiology of myeloma. In this study, we found only one DNA repair gene that was differentially expressed between FGFR3-positive and -negative cases, APEX2. This is in keeping with our previous data where we used a quantitative TaqMan PCR approach to explore the patterns of DSB repair genes in a larger series of cases (33) . This study included a number of important members of the NHEJ pathway that are not present on the Affymetrix U95Av2 chip. Expression of these genes was similar between cases with and without a t(4;14) translocation, suggesting that there are distinct patterns of gene expression that distinguish myeloma plasma cells from other lymphoid malignant disease, but the differences between cases of myeloma are limited.
In conclusion, using RT-PCR and gene analysis, we demonstrate that cases with a t(4;14) have a distinct gene expression pattern compared with other cases of myeloma. Importantly a number of pathways are dysregulated as a consequence of the t(4;14) in multiple myeloma, and two genes, WHSC1/MMSET and cyclin D2, appear to play a central role and may account for the poor prognosis associated with this translocation. Interestingly, 25% of myeloma cases lacking evidence of a translocation by RT-PCR also had up-regulation of a MMSET transcript to the same level as cases with a translocation, suggesting that this gene plays an important role in myeloma pathogenesis.
FOOTNOTES
Grant support: Supported by the Leukaemia Research Fund United Kingdom (F. Davies, G. Morgan), Department of Health (F. Davies, K. Rees-Unwin), Yorkshire Cancer Research (D. Gonzalez, G. Morgan), British Society of Haematology (A. Rawstrom, F. Davies), and Doris Duke Distinguished Clinical Research Scientist Award (K. Anderson).
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org); A. Dring and F. Davies contributed equally to this work.
Requests for reprints: Faith Davies, Academic Unit of Haematology and Oncology, Algernon Firth Building, School of Medicine, University of Leeds, Leeds, United Kingdom LS2 9JT. Phone/Fax: 44-113-343-3372; E-mail: F.E.Davies{at}leeds.ac.uk
5 Internet address for DNA-Chip Analyzer (dChip): www.dchip.org. 
6 See Supplementary Data for this article at http://cancerres.aacrjournals.org.
Received 3/ 8/04; revised 5/20/04; accepted 6/ 2/04.
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