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
Source: PubMed


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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Available from: Luca Agnelli
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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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    ABSTRACT: The identification of overexpressed miRNAs in multiple myeloma (MM) has progressively added a further level of complexity to MM biology. miRNA and gene expression profiles of two large representative MM datasets, available from retrospective and prospective series and encompassing a total of 249 patients at diagnosis, were analyzed by means of in silico integrative genomics methods, based on MAGIA2 and Micrographite computational procedures. We first identified relevant miRNA/transcription factors/target gene regulation circuits in the disease and linked them to biological processes. Members of the miR-99b/let-7e/miR-125a cluster, or of its paralog, upregulated in t(4;14), were connected with the specific transcription factors PBX1 and CEBPA and several target genes. These results were validated in two additional independent plasma cell tumor datasets. Then, we reconstructed a non-redundant miRNA-gene regulatory network in MM, linking miRNAs, such as let-7g, miR-19a, mirR-20a, mir-21, miR-29 family, miR-34 family, miR-125b, miR-155, miR-221 to pathways associated with MM subtypes, in particular the ErbB, the Hippo, and the Acute myeloid leukemia associated pathways.
    Preview · Article · Oct 2015 · Oncotarget
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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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    ABSTRACT: MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc.
    Full-text · Article · Sep 2011 · Cell
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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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    ABSTRACT: Polo-like kinases (PLKs) play an important role in cell cycle progression, checkpoint control and mitosis. The high mitotic index and chromosomal instability of advanced cancers suggest that PLK inhibitors may be an attractive therapeutic option for presently incurable advanced neoplasias with systemic involvement, such as multiple myeloma (MM). We studied the PLK 1, 2, 3 inhibitor BI 2536 and observed potent (IC50<40 nM) and rapid (commitment to cell death <24 hrs) in vitro activity against MM cells in isolation, as well as in vivo activity against a traditional subcutaneous xenograft mouse model. Tumor cells in MM patients, however, don't exist in isolation, but reside in and interact with the bone microenvironment. Therefore conventional in vitro and in vivo preclinical assays don't take into account how interactions between MM cells and the bone microenvironment can potentially confer drug resistance. To probe this question, we performed tumor cell compartment-specific bioluminescence imaging assays to compare the preclinical anti-MM activity of BI 2536 in vitro in the presence vs. absence of stromal cells or osteoclasts. We observed that the presence of these bone marrow non-malignant cells led to decreased anti-MM activity of BI 2536. We further validated these results in an orthotopic in vivo mouse model of diffuse MM bone lesions where tumor cells interact with non-malignant cells of the bone microenvironment. We again observed that BI 2536 had decreased activity in this in vivo model of tumor-bone microenvironment interactions highlighting that, despite BI 2536's promising activity in conventional assays, its lack of activity in microenvironmental models raises concerns for its clinical development for MM. More broadly, preclinical drug testing in the absence of relevant tumor microenvironment interactions may overestimate potential clinical activity, thus explaining at least in part the gap between preclinical vs. clinical efficacy in MM and other cancers.
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