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Gene expression profiling of plasma cell dyscrasias reveals molecular patterns associated with distinct IGH translocations in multiple myeloma. Oncogene 24, 2461-2473

Laboratorio di Ematologia Sperimentale e Genetica Molecolare and U.O. Ematologia 1, Dipartimento di Scienze Mediche, Università degli Studi di Milano, Ospedale Maggiore IRCCS, Milano, Italy.
Oncogene (Impact Factor: 8.46). 05/2005; 24(15):2461-73. DOI: 10.1038/sj.onc.1208447
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ABSTRACT

Multiple myeloma (MM) is the most common form of plasma cell dyscrasia, characterized by a marked heterogeneity of genetic lesions and clinical course. It may develop from a premalignant condition (monoclonal gammopathy of undetermined significance, MGUS) or progress from intramedullary to extramedullary forms (plasma cell leukemia, PCL). To provide insights into the molecular characterization of plasma cell dyscrasias and to investigate the contribution of specific genetic lesions to the biological and clinical heterogeneity of MM, we analysed the gene expression profiles of plasma cells isolated from seven MGUS, 39 MM and six PCL patients by means of DNA microarrays. MMs resulted highly heterogeneous at transcriptional level, whereas the differential expression of genes mainly involved in DNA metabolism and proliferation distinguished MGUS from PCLs and the majority of MM cases. The clustering of MM patients was mainly driven by the presence of the most recurrent translocations involving the immunoglobulin heavy-chain locus. Distinct gene expression patterns have been found to be associated with different lesions: the overexpression of CCND2 and genes involved in cell adhesion pathways was observed in cases with deregulated MAF and MAFB, whereas genes upregulated in cases with the t(4;14) showed apoptosis-related functions. The peculiar finding in patients with the t(11;14) was the downregulation of the alpha-subunit of the IL-6 receptor. In addition, we identified a set of cancer germline antigens specifically expressed in a subgroup of MM patients characterized by an aggressive clinical evolution, a finding that could have implications for patient classification and immunotherapy.

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    • "So far, little is known about the TFs involved in t(4;14)- associated circuits in myeloma. PBX1 has been largely described in acute lymphoblastic leukemia; notably, it has been suggested that, in complex with MEIS2, PBX1 is involved in transcriptional regulation mediated by KLF4, which has been previously shown by us as specifically overexpressed in t(4;14) patients[24,25]. Upregulation of CEBPA has been linked to favorable prognosis in both adult and pediatric acute myeloid leukemia patients. "
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    • "(A) Structures of the BET bromodomain inhibitors JQ1 and iBET. (B,C) Expression levels (log2 transformed, median-centered values) for BRD4 transcripts were evaluated in oligonucleotide microarray data from normal plasma cells (NPCs) from healthy donors, individuals with MGUS or SMM patients (panel B, dataset GSE5900, (Zhan et al., 2007)); and in plasma cells from MGUS, MM and PCL patients (panel C, dataset GSE2113 (Mattioli et al., 2005)). Increased BRD4 expression is observed in SMM (or MGUS) compared to NPCs (panel B) and in PCL compared to MM (panel C) (nonparametric Kruskal-Wallis one-way analysis of variance p< 0.001 and p=0.0123, respectively; Dunn's Multiple Comparison post-hoc tests p<0.05, in both cases). "
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    • "Gene expression data from publicly available Gene Expression Omnibus (GEO) datasets (accession numbers GSE19784, GSE2113, GSE2658 and GSE8546) were downloaded and analyzed through Oncomine 4.4 (for datasets GSE2658 and GSE8546) or directly from GEO (datasets GSE19784 and GSE2113). These datasets included profiles of CD138+ myeloma cells from patients enrolled in the Dutch HOVON trial (N = 320, GSE19784) [23]; CD138+ plasma cells from patients with monoclonal gammopathy of undetermined significance (MGUS), myeloma or plasma cell leukemia (7, 39 and 6 cases respectively, N = 52 total, GSE2113) [24]; CD138+ myeloma cells from 414 newly diagnosed MM patients (GSE2658) [25]; and CD138+ myeloma cells from 174 cases prior to initiation of therapy vs. 55 cases after disease recurrence (N = 229 total, GSE8546) [26]. Using one-way ANOVA analysis, we evaluated the absolute expression of various probes for PLK1, 2, 3 and 4 (GSE19784); the differences in expression of PLK1 transcript in MGUS, MM and PCL (GSE2113); as well as the differences in log2-transformed median-centered transcript levels, in the GSE19784 dataset [23] for PLK1 in various molecularly defined subtypes of MM [25]. "
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