The molecular characterization and clinical management of multiple myeloma in the post-genome era

Donna D and Donald M Lambert Laboratory for Myeloma Genetics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K (Impact Factor: 10.43). 09/2009; 23(11):1941-56. DOI: 10.1038/leu.2009.160
Source: PubMed


Cancer-causing mutations disrupt coordinated, precise programs of gene expression that govern cell growth and differentiation. Microarray-based gene-expression profiling (GEP) is a powerful tool to globally analyze these changes to study cancer biology and clinical behavior. Despite overwhelming genomic chaos in multiple myeloma (MM), expression patterns within tumor samples are remarkably stable and reproducible. Unique expression patterns associated with recurrent chromosomal translocations and ploidy changes defined molecular classes with differing clinical features and outcomes. Combined molecular techniques also dissected two distinct, reproducible forms of hyperdiploid disease and have molecularly defined MM with high risk for poor clinical outcome. GEP is now used to risk-stratify patients with newly diagnosed MM. Groups with high-risk features are evident in all GEP-defined MM classes, and GEP studies of serial samples showed that risk increases over time, with relapsed disease showing dramatic GEP shifts toward a signature of poor outcomes. This suggests a common mechanism of disease evolution and potentially reflects preferential expansion of therapy-resistant cells. Correlating GEP-defined disease class and risk with outcomes of therapeutic regimens reveals class-specific benefits for individual agents, as well as mechanistic insights into drug sensitivity and resistance. Here, we review modern genomics contributions to understanding MM pathogenesis, prognosis, and therapy.

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    • "Here we have documented (Table 3) that the prognosis for patients assigned with a melphalan RI >75% was independent of the ISS prognostic staging system [5]. The best described prognostic gene signatures seem to be from the University of Arkansas for Medical Sciences (UAMS), the Intergroup Francophone du Myeloma (IFM) and the HOVON prognostic classification gene lists [16], [26], [29]–[31] and we extended the multivariate Cox proportional hazard analysis by including the UAMS high risk signature as a variable and showed that the melphalan RI is also independent of this index when considering outcome as PFS and OS (Table S1). Finally and most importantly, the so-called predictive classification should be able to estimate individual outcome of a specific therapeutic intervention and allow for selection and elimination of specific drugs. "
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    ABSTRACT: In a conceptual study of drug resistance we have used a preclinical model of malignant B-cell lines by combining drug induced growth inhibition and gene expression profiling. In the current report a melphalan resistance profile of 19 genes were weighted by microarray data from the MRC Myeloma IX trial and time to progression following high dose melphalan, to generate an individual melphalan resistance index. The resistance index was subsequently validated in the HOVON65/GMMG-HD4 trial data set to prove the concept. Biologically, the assigned resistance indices were differentially distributed among translocations and cyclin D expression classes. Clinically, the 25% most melphalan resistant, the intermediate 50% and the 25% most sensitive patients had a median progression free survival of 18, 32 and 28 months, respectively (log-rank P-value = 0.05). Furthermore, the median overall survival was 45 months for the resistant group and not reached for the intermediate and sensitive groups (log-rank P-value = 0.003) following 38 months median observation. In a multivariate analysis, correcting for age, sex and ISS-staging, we found a high resistance index to be an independent variable associated with inferior progression free survival and overall survival. This study provides clinical proof of concept to use in vitro drug screen for identification of melphalan resistance gene signatures for future functional analysis.
    PLoS ONE 12/2013; 8(12):e83252. DOI:10.1371/journal.pone.0083252 · 3.23 Impact Factor
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    • "Multiple myeloma displays a high genomic instability [8] which is observed in other types of cancer and is known to be affected by over-expression of cyclin E [14], [16]. To determine the expression profile of CCNE1 in hMMCLs, cells were extracted, and the level of the protein verified by immunoblotting (Figure 1A). "
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    ABSTRACT: Multiple Myeloma (MM) is a lymphatic neoplasm characterized by clonal proliferation of malignant plasma cell that eventually develops resistance to chemotherapy. Drug resistance, differentiation block and increased survival of the MM tumor cells result from high genomic instability. Chromosomal translocations, the most common genomic alterations in MM, lead to dysregulation of cyclin D, a regulatory protein that governs the activation of key cell cycle regulator--cyclin dependent kinase (CDK). Genomic instability was reported to be affected by over expression of another CDK regulator--cyclin E (CCNE). This occurs early in tumorigenesis in various lymphatic malignancies including CLL, NHL and HL. We therefore sought to investigate the role of cyclin E in MM. CCNE1 expression was found to be heterogeneous in various MM cell lines (hMMCLs). Incubation of hMMCLs with seliciclib, a selective CDK-inhibitor, results in apoptosis which is accompanied by down regulation of MCL1 and p27. Ectopic over expression of CCNE1 resulted in reduced sensitivity of the MM tumor cells in comparison to the paternal cell line, whereas CCNE1 silencing with siRNA increased the cell sensitivity to seliciclib. Adhesion to FN of hMMCLs was prevented by seliciclib, eliminating adhesion-mediated drug resistance of MM cells. Combination of seliciclib with flavopiridol effectively reduced CCNE1 and CCND1 protein levels, increased subG1 apoptotic fraction and promoted MM cell death in BMSCs co-culture conditions, therefore over-coming stroma-mediated protection. We suggest that seliciclib may be considered as essential component of modern anti MM drug combination therapy.
    PLoS ONE 04/2012; 7(4):e33856. DOI:10.1371/journal.pone.0033856 · 3.23 Impact Factor
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    • "There is also a high variability with regards to the clinical outcome of the patients in response to chemotherapy, with survival ranging from a few weeks to more than 10 years [1]. Combined studies of the genotype, phenotype and response to treatment illustrate this now wellknown concept of many and multiple myelomas [2] [3]. Despite heterogeneity and new treatments, MM remains a fatal disease, suggesting that resistant MM cells are rarely eradicated. "
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    ABSTRACT: The purpose of this study was to identify the pathways associated with the ability of CD138(+) human myeloma cells to form colonies in a serum-free semi-solid human collagen-based assay. Only 26% (7 of 27) of human myeloma cell lines were able to spontaneously form colonies. This spontaneous clonogenic growth correlated with the expression of the NOTCH ligand JAG2 (p<0.001). Blocking JAG-NOTCH interactions with NOTCH-Fc chimeric molecules impaired self-colony formation, indicating a role for JAG-NOTCH pathway in colony formation. In two cell lines, silencing of JAG2 blocked both colony formation and in vivo tumor formation in immunocompromised mice. RT-PCR and flow cytometry analysis revealed that JAG2 is often expressed by CD138(+) primary cells. Our results indicate that spontaneous clonogenic growth of myeloma cells requires the expression of JAG2.
    Blood Cells Molecules and Diseases 02/2012; 48(4):247-53. DOI:10.1016/j.bcmd.2012.01.006 · 2.65 Impact Factor
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