A global expression-based analysis of the consequences of the t(4;14) translocation in myeloma.
OBJECTIVE
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.


METHODS
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.
Dring
Ann M
AM
Academic Unit of Haematology and Oncology, University of Leeds, Leeds, United Kingdom.
Davies
Faith E
FE
Fenton
James A L
JA
Roddam
Philippa L
PL
Scott
Kathryn
K
Gonzalez
David
D
Rollinson
Sara
S
Rawstron
Andrew C
AC
Rees-Unwin
Karen S
KS
Li
Cheng
C
Munshi
Nikhil C
NC
Anderson
Kenneth C
KC
Morgan
Gareth J
GJ
D017398:Alternative Splicing; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014178:Translocation, Genetic
D014408:Biomarkers, Tumor; C115494:IgH-MMSET fusion protein, human; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017468:Receptors, Fibroblast Growth Factor; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3