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

涉及免疫球蛋白重链(IGH)基因14q32.3及其配对基因的染色体易位与B细胞恶性肿瘤的发病机制和临床特征有关。为明确14q32.3易位与特定癌基因座的关系，我们采用双色荧光原位杂交(DC-FISH)技术对113例MM患者进行了分析。DC-FISH检测的105例患者中，IgH基因(14q32.3)与c-MYC(8q24.1)、CCND1(11q13.3)、FGFR3(4p15)、MUM1/IRF4(6p25)、bcl2(18q21)基因探针联合检测，69例(66%)发生了IgH易位。染色体t(11；14)检出27例(71%)为CCND1与IgH探针的融合信号，t(8；14)为c-myc与IgH的融合信号，t(6；14)为8例(21%)MUM1与IgH的融合信号。43例患者中有9例(21%)检出双IgH易位。CCND_1/IgH重排与浆细胞白血病或MM的白血病表现相关C-myc/IgH Rea…更多的争吵与侵袭性疾病有关。FGFR3/IgH重排患者常出现溶骨性病变，根据细胞表面免疫表型分为三类：前B细胞(CD38+、CD19-)、未成熟浆细胞(CD38+、CD19-、MPC-)和成熟浆细胞(CD38+、CD19-、MPC+)。15例患者的前B细胞均未参与IgH易位。我们根据携带高易位的细胞群体定义了三种不同的模式：未成熟(-)和成熟(+)，未成熟(+)和成熟(+)，以及未成熟(-f)和成熟(-)。FGFRs阳性患者表现为三种模式，而c-MYC或CCND1阳性患者未表现为未成熟(+)/成熟(-)模式。目前的研究表明，单个IgH易位可以将正常细胞转化为骨髓瘤细胞，FGFR3/IgH易位在骨髓瘤形成过程中既是主要事件，也是辅助事件。此外，c-myc/IgH或FGFR3/IgH易位的获得可能与疾病的进展有关。较少

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