Dysregulation of oncogenes by translocation to the IgH locus (14q32) is a seminal event in the pathogenesis of B-cell tumours 1 . In multiple myeloma (MM), translocations to the IgH locus have been reported at an incidence of 20-60%. For most translocations, the partner chromosome is unknown (14q+); for the others, a diverse array of chromosomal partners have been identified, with 11q13 (cyclin D1) the only chromosome that is frequently involved [2][3][4][5][6] . Recently, we developed a Southern-blot assay that detects translocation breakpoint fragments in most MM tumours, including those with no translocation detected by conventional karyotyping 6 . In a continuing analysis of translocations in 21 myeloma cell lines and primary tumours, we show that the novel, karyotypically silent translocation t(4;14)(p16.3;q32.3) is present in five lines and at least three of ten primary tumours. The chromosome-4 breakpoints are clustered in a 70-kb region centromeric to the fibroblast growth factor receptor 3 gene (FGFR3), the apparent dysregulated oncogene. Two lines and one primary tumour with this translocation selectively express an FGFR3 allele containing activating mutations identified previously in thanatophoric dwarfism. We propose that after the t(4;14) translocation, somatic mutation during tumour progression frequently generates an FGFR3 protein that is active in the absence of ligand.As described in detail elsewhere 6 , we generated paired probes immediately upstream and downstream of the repetitive sequences in each switch region-for example, 5'Sµ and 3'Sµ probes. By Southern-blot analysis, candidate translocation breakpoint fragments were identified as rearranged fragments that hybridize to only one switch probe. Fig. 1a illustrates a balanced translocation into Sµ, with the 3'Sµ probe detecting the der(14) breakpoint and the 5'Sµ probe detecting the der(4) breakpoint. Using this approach, we cloned one translocation breakpoint fragment involving chromosome 4 from each of five samples: four MM lines (KMS11, H929, OPM2 and JIM3) and one plasma cell leukaemia tumour (PCL-1). In each case, the novel non-Ig sequences at the breakpoint and at one end of the fragment were identical to sequences present in a cosmid contig that is centromeric to the fibroblast growth factor receptor 3 (FGFR3) gene at 4pl6.3 (Fig. 1) probes that were used in Southern-blot analyses to detect and map reciprocal breakpoint fragments for KMS11, H929 and PCL-1 (Fig. 2a-c). For example, as shown in Fig. 2a for the der(4)(5'Sµ) reciprocal breakpoint in KMS11 ( Fig. 1), a 5'Sµ probe detected a rearranged 7.9-kb XbaI fragment (compared to 7.5-kb fragment in placental [P] DNA) and a 4pl6.3 probe (9226 in Fig. 1b) that detects a 13.8-kb germline fragment in the tumour and in placental DNA, co-hybridizes to the 7.9-kb XbaI fragment in KMS11. These results, together with Southern blots using other enzymes, are consistent with the der(4) (5'Sµ) translocation breakpoint occurring near the cloned der(14) (3'Sµ) translocation breakpoint for K...