A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains anIGH/MMSET fusion transcript

Abstract

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 trans-

Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074

“…However, this line has been reported to express FGFR3 only very weakly, 19 and to harbour a Ras rather than a FGFR3 mutation. 9 This is consistent with recent data suggesting that up to 30% of IgH-MMSET-positive MM patients are FGFR3-expression negative 20,21 and explains the absence of an inhibitory effect by SU5402 or PD173074.…”

An update on molecular biology and drug resistance mechanisms of multiple myeloma

“…The second most common translocation is t(4:14)(p16;q32) (Chesi et al, 1998;Santra et al, 2003). This translocation involves Wolf-Hirschhorn syndrome candidate 1 gene (WHSC1) and fibroblast growth factor receptor 3 (FGFR3), which is an oncogenic receptor tyrosine kinase gene (Kuehl and Bergsagel, 2002).…”

Genetic heterogeneity in multiple myeloma

“…15,25,34 A similar association has been demonstrated between chromosome 13 and nonhyperdiploidy. 5,26 Whereas monosomy 13 is observed in 30-35% of the patients with an hyperdiploid karyotype, it is present in about 85% of nonhyperdiploid patients. Finally, correlation of 14q32 translocations with ploidy revealed interesting findings.…”

“…Two reports did show that FGFR3 was not always overexpressed in PC with the t(4;14), focusing the major role on MMSET. 25,26 So far, the physiological role of MMSET is not known. As it contains a SET domain, this protein may play a role in the control of chromatin conformation.…”