Chromosomal abnormalities are present in most (if not all) patients with multiple myeloma (MM) and primary plasma cell leukemia (PCL). Furthermore, recent data have shown that numerical chromosomal changes are present in most individuals with monoclonal gammopathy of undetermined significance (MGUS). Epidemiological studies have shown that up to one third of MM may emerge from pre-existing MGUS. To clarify further possible stepwise chromosomal aberrations on a pathway between MGUS and MM, we have analyzed 158 patients with either MM or primary PCL and 19 individuals with MGUS using fluorescence in situ hybridization (FISH). Our FISH analyses were designed to detect illegitimate IGH rearrangements at 14q32 or monosomy 13. Whereas translocations involving the 14q32 region were observed with a similar incidence (60%) in both conditions, a significant difference was found in the incidence of monosomy 13 in MGUS versus MM or primary PCL. It was present in 40% of MM/PCL patients, but in only 4 of 19 MGUS individuals. Moreover, whereas monosomy 13 was found in the majority of plasma cells in MM, it was observed only in cell subpopulations in MGUS. It is noteworthy that, in a group of 20 patients with MM and a previous MGUS history, incidence of monosomy 13 was 70% versus 31% in MM patients without a known history of MGUS (P = .002). Thus, this study highlights monosomy 13 as correlated with the transformation of MGUS to overt MM and may define 2 groups of MM with possible different natural history and outcome, ie, post-MGUS MM with a very high incidence of monosomy 13 and de novo MM in which other genetic events might be involved. Serial analyses of individuals with MGUS will be needed to validate this model.
Genetic alterations concerning the genes coding for cell cycle regulatory proteins have been described associated with B-chronic lymphoproliferative disorders. Most of them involve the pRb pathway and peculiarly the cyclin D1 protein that regulates the progression through the G1 phase and the G1 to S phase transition.1 In a recent paper, with the use of Northern blot technique, Suzuki and coworkers 2 described that cyclin D1 expression was observed in a majority of mantle cell lymphomas (MCL, 13/19), in a subset of B-chronic lymphocytic leukemias (B-CLL, 2/11) and in one out of six multiple myelomas (MM). In all cases but the MM, cyclin D1 expression was associated with the translocation t(11;14)(q13;q32) which joined the CCND1 locus encompassing the cyclin D1 coding gene with immunoglobulin heavy chain locus. Moreover, they described that cyclin D3 mRNA was ubiquitously expressed in B cell malignancies but restricted to cyclin D1 non-expressing cells when cyclin D2 mRNA was always present. We have also studied a series of 127 patients, with B-chronic lymphoproliferative disorders, using a very sensitive and reliable competitive RT-PCR technique, 3 followed by Western blotting. 4 In this series, cyclin D1 over-expression was detected in all patients with MCL (10/10), in a very few number of B-CLL (4/111), in hairy cell leukemias (HCL, 3/5) and in one out of one B-large cell lymphoma (BLCL). 4 We have now extended this study and analyzed by the same techniques 23 MCL, 174 B-CLL, 17 splenic lymphomas with villous lymphocytes (SLVL), 52 MM, four HCL, two B-prolymphocytic leukemias (B-PLL), five Waldenströ m's diseases (WD), three lymphoplasmocytic leukemias (LPL), and one follicular lymphoma (FL). By densitometric analysis of electrophoresed PCR fragments, 4 we have analyzed the relative intensity of each cyclin D product. We defined an over-expression of cyclin D1 when the intensity of cyclin D1 product was higher to those of cyclin D2 and D3
8539 MicroRNA, a small endogenous RNA regulating specific expressed gene function has been implicated in normal biological processes as well as in malignant transformation. Here we have investigated the role of microRNAs in multiple myeloma (MM) biology, and their influence on prognosis and clinical outcome. We evaluated profiles of 384 microRNAs in CD138+ MM cells from 79 patients with MM, 11 cell lines and 9 healthy donors using qRT-PCR based microRNA array. We detected significant modulation of expression of 61 microRNAs in myeloma cells compared to normal plasma cells. Unsupervised hierarchical clustering of filtered matured microRNAs, identified two major groups within the MM population (groups A and group B). Group A clustered with MM cell lines, indicating more aggressive course of disease. Within B group, second degree node, group B2, clustered with normal plasma cells indicating indolent course. The unsupervised clustering of all MM samples showed consistent change in miR-146b, -140, -145, -125a, -151, -223, -155, let-7f, indicative of a role of these microRNA in myelomagenesis; while supervised analysis of samples within groups A and B identified modulated expression of different sets of miRNAs. In group A miR585 and let-7f were upregulated 8–12 fold; in group B, all differentially expressed microRNAs were downregulated (p<0.001) compared to normal plasma cells. These modulated miRNAs target critical signaling molecules such as HOX9, c-myc, Bcl-2, SHP1 and SHP2. We further analyzed the effect of microRNA on clinical outcome. We have observed significantly superior event free and overall survival of patients in group B compared to patients ingroup A (2 yr estimated EFS 79% versus 54% respectively; p=0.05; and 2 yr estimated OS 94% versus 70% respectively; p =0.017). Functional analysis by modulating miRNAs 585, 155 and let-7f showed change in levels of predicted genes with consequent biological effect on growth and apoptosis in MM cell line. Taken together, this data identifies miRNAs as critical modulators of gene expression and signaling pathways and provides potential novel targets in MM to both understand biological behavior and for therapeutic application. No significant financial relationships to disclose.
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