A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript.
Previous studies have revealed that that approximately 10% to 15% of multiple myelomas (MMs) are characterized by a reciprocal t(4;14)(p16;q32) translocation that activates expression of FGFR3 and creates an IGH/MMSET fusion transcript. Current data suggest that activation of FGFR3 is the oncogenic consequence of this rearrangement. Using a combination of microarray profiling, reverse transcriptase-polymerase chain reaction (RT-PCR), and interphase fluorescence in situ hybridization (FISH), we show that 32 (18%) of 178 newly diagnosed cases of MM harbor the t(4;14)(p16;q32). Importantly, 32% of these cases lack expression of FGFR3, yet express MMSET and have an IGH/MMSET fusion transcript. Interphase FISH showed that whereas the IGH/MMSET fusion was present in more than 80% of the clonotypic plasma cells in these novel cases, there was typically a complete loss of one copy of FGFR3. These data indicate that the t(4;14)(p16;q32) and loss of FGFR3 occurred at a very early stage and suggest that activation of MMSET, not FGFR3, may be the critical transforming event of this recurrent translocation.
Santra
Madhumita
M
Donna and Donald Lambert Laboratory of Myeloma Genetics at the Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Zhan
Fenghuang
F
Tian
Erming
E
Barlogie
Bart
B
Shaughnessy
John
J
D001853:Bone Marrow / Q000737:chemistry; D002883:Chromosomes, Human, Pair 14; D002894:Chromosomes, Human, Pair 4; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009101:Multiple Myeloma / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger / Q000032:analysis; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014178:Translocation, Genetic
C115494:IgH-MMSET fusion protein, human; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3