SUBCLASSFICIATION OF MULTIPLE MYELOMA BASED ON THE PARTNER GENES OF TUMOR-SPECIFIC IMMUNOGLOBULIN HEAVY CHAIN GENE TRANSLOCATION BY USING DOUBLE-COLOR FLUORESCENCE IN SITU HYBRIDIZATION

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Chromosomal translocation involving the immunoglobulin heavy chain (IGH) gene at band 14q32.3 and its partner genes are implicated in both the pathogenesis and clinical characteristics of B-cell malignancies. To define the incidence of 14q32.3 translocation with specific oncogene loci, we analyzed 113 patients with MM by double-color fluorescence in situ hybridization (DC-FISH). Using the IGH gene (14q32.3) in combination with c-MYC (8q24.1), CCND1 (11q13.3), FGFR3 (4p15), MUM1/IRF4(6p25), and BCL2 (18q21) gene probes detected IGH translocations in 69 (66 %) of 105 patients who were assessed by DC-FISH. Chromosome t(11 ; 14) was detected in 27 (71 %) of 38 patients as fusion signal of CCND1 with IGH probes; t(8 ; 14) in 11 (31 %) of 35 as fusion of c-MYC with IGH ; and t(6 ; 14) in 8 (21 %) of 38 as MUM1 with IGH. Double IGH translocation was detected 9 (21 %) of 43 patients. CCND1/IGH rearrangement was associated with plasma cell leukemia or leukemia manifestation of MM. C-MYC/IGH rea … More rrangement was associated with aggressive disease. Lytic bone lesion was frequently found in patients with FGFR3/IGH rearrangement.Three distinct cell populations were defined based on the surface immunophenotype ; pre-B cell (CD38+, CD19-), immature plasma cell (CD38+, CD19-, MPC-), and mature plasma cell (CD38+, CD19-, MPC+). Pre-B cells were not involved in IGH translocation in all 1 5 patients analyzed. We defined three distinct patterns based on cell populations carrying IGH translocation; immature(-) and mature(+), immature(+) and mature(+) , and immature(-f) and mature(-). FGFRS-positive patients demonstrated all three patterns, whereas c-MYC- or CCND1-positive patients did not showed immature(+)/mature(-) pattern. The present studies suggest that single IGH translocation can transform normal cells to myeloma cells and that FGFR3/IGH translocation occurs as both primary and additional event during the myelomagenesis. Furthermore, acquisition of c-MYC/IGH or FGFR3/IGH translocation may be associated with progression of the diseases. Less