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ABSTRACT: IL-6 signaling can be enhanced through transsignaling by the soluble IL-6 receptor (sIL-6r), allowing for the pleiotropic cytokine to affect cells it would not ordinarily have an effect on. Serum levels of sIL-6r can be used as an independent prognostic indicator and further stratify the GEP 70-gene low-risk group to identify an intermediate-risk group in multiple myeloma (MM). By analyzing more than 600 MM patients with ELISA, genotyping, and gene expression profiling tools, we show how the combination of 2 independent molecular genetic events is related to synergistic increases in sIL-6r levels. We also show that the rs2228145 minor allele is related to increased expression levels of an IL-6r splice variant that purportedly codes exclusively for a sIL-6r isoform. Together, the SNP rs2228145 minor allele C and amplification of chromosome 1q21 are significantly correlated to an increase in sIL-6r levels, which are associated with lower overall survival in 70-gene low-risk disease, and aid in identification of the intermediate-risk MM group.
Blood 11/2011; 119(2):503-12. · 9.90 Impact Factor
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Yiming Zhou,
Lijuan Chen,
Bart Barlogie,
Owen Stephens,
Xiaosong Wu, David R Williams,
Marie-Astrid Cartron,
Frits van Rhee,
Bijay Nair,
Sarah Waheed,
Mauricio Pineda-Roman,
Yazan Alsayed,
Elias Anaissie,
John D Shaughnessy
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ABSTRACT: MicroRNAs (miRNAs) are noncoding RNAs that regulate global gene expression. miRNAs often act synergistically to repress target genes, and their dysregulation can contribute to the initiation and progression of a variety of cancers. The clinical relationship between global expression of miRNA and mRNA in cancer has not been studied in detail. We used whole-genome microarray analyses of CD138-enriched plasma cells from 52 newly diagnosed cases of multiple myeloma to correlate miRNA expression profiles with a validated mRNA-based risk stratification score, proliferation index, and predefined gene sets. In stark contrast to mRNAs, we discovered that all tested miRNAs were significantly up-regulated in high-risk disease as defined by a validated 70-gene risk score (P < 0.01) and proliferation index (P < 0.05). Increased expression of EIF2C2/AGO2, a master regulator of the maturation and function of miRNAs and a component of the 70-gene mRNA risk model, is driven by DNA copy number gains in MM. Silencing of AGO2 dramatically decreased viability in MM cell lines. Genome-wide elevated expression of miRNAs in high-risk MM may be secondary to deregulation of AGO2 and the enzyme complexes that regulate miRNA maturation and function.
Proceedings of the National Academy of Sciences 04/2010; 107(17):7904-9. · 9.68 Impact Factor
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Christina M Annunziata,
R Eric Davis,
Yulia Demchenko,
William Bellamy,
Ana Gabrea,
Fenghuang Zhan,
Georg Lenz,
Ichiro Hanamura,
George Wright,
Wenming Xiao, [......],
Bruce Tan,
Hong Zhao,
Owen Stephens,
Madhumita Santra, David R Williams,
Lenny Dang,
Bart Barlogie,
John D Shaughnessy,
W Michael Kuehl,
Louis M Staudt
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ABSTRACT: Mechanisms of constitutive NF-kappaB signaling in multiple myeloma are unknown. An inhibitor of IkappaB kinase beta (IKKbeta) targeting the classical NF-kappaB pathway was lethal to many myeloma cell lines. Several cell lines had elevated expression of NIK due to genomic alterations or protein stabilization, while others had inactivating mutations of TRAF3; both kinds of abnormality triggered the classical and alternative NF-kappaB pathways. A majority of primary myeloma patient samples and cell lines had elevated NF-kappaB target gene expression, often associated with genetic or epigenetic alteration of NIK, TRAF3, CYLD, BIRC2/BIRC3, CD40, NFKB1, or NFKB2. These data demonstrate that addiction to the NF-kappaB pathway is frequent in myeloma and suggest that IKKbeta inhibitors hold promise for the treatment of this disease.
Cancer Cell 09/2007; 12(2):115-30. · 26.57 Impact Factor
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John D Shaughnessy,
Fenghuang Zhan,
Bart E Burington,
Yongsheng Huang,
Simona Colla,
Ichiro Hanamura,
James P Stewart,
Bob Kordsmeier,
Christopher Randolph, David R Williams, [......],
Abid Mohiuddin,
Mauricio Pineda-Roman,
Guido Tricot,
Frits van Rhee,
Jeffrey Sawyer,
Yazan Alsayed,
Ronald Walker,
Maurizio Zangari,
John Crowley,
Bart Barlogie
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ABSTRACT: To molecularly define high-risk disease, we performed microarray analysis on tumor cells from 532 newly diagnosed patients with multiple myeloma (MM) treated on 2 separate protocols. Using log-rank tests of expression quartiles, 70 genes, 30% mapping to chromosome 1 (P < .001), were linked to early disease-related death. Importantly, most up-regulated genes mapped to chromosome 1q, and down-regulated genes mapped to chromosome 1p. The ratio of mean expression levels of up-regulated to down-regulated genes defined a high-risk score present in 13% of patients with shorter durations of complete remission, event-free survival, and overall survival (training set: hazard ratio [HR], 5.16; P < .001; test cohort: HR, 4.75; P < .001). The high-risk score also was an independent predictor of outcome endpoints in multivariate analysis (P < .001) that included the International Staging System and high-risk translocations. In a comparison of paired baseline and relapse samples, the high-risk score frequency rose to 76% at relapse and predicted short postrelapse survival (P < .05). Multivariate discriminant analysis revealed that a 17-gene subset could predict outcome as well as the 70-gene model. Our data suggest that altered transcriptional regulation of genes mapping to chromosome 1 may contribute to disease progression, and that expression profiling can be used to identify high-risk disease and guide therapeutic interventions.
Blood 03/2007; 109(6):2276-84. · 9.90 Impact Factor
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Fenghuang Zhan,
Bart Barlogie,
Varant Arzoumanian,
Yongsheng Huang, David R Williams,
Klaus Hollmig,
Mauricio Pineda-Roman,
Guido Tricot,
Frits van Rhee,
Maurizio Zangari,
Madhav Dhodapkar,
John D Shaughnessy
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ABSTRACT: Monoclonal gammopathy of undetermined significance (MGUS) can progress to multiple myeloma (MM). Although these diseases share many of the same genetic features, it is still unclear whether global gene-expression profiling might identify prior genomic signatures that distinguish them. Through significance analysis of microarrays, 52 genes involved in important pathways related to cancer were differentially expressed in the plasma cells of healthy subjects (normal plasma-cell [NPC]; n=22) and patients with stringently defined MGUS/smoldering MM (n=24) and symptomatic MM (n=351) (P<.001). Unsupervised hierarchical clustering of 351 patients with MM, 44 with MGUS (24+20), and 16 with MM from MGUS created 2 major cluster branches, one containing 82% of the MGUS patients and the other containing 28% of the MM patients, termed MGUS-like MM (MGUS-L MM). Using the same clustering approach on an independent cohort of 214 patients with MM, 27% were found to be MGUS-L. This molecular signature, despite its association with a lower incidence of complete remission (P=.006), was associated with low-risk clinical and molecular features and superior survival (P<.01). The MGUS-L signature was also seen in plasma cells from 15 of 20 patients surviving more than 10 years after autotransplantation. These data provide insight into the molecular mechanisms of plasma-cell dyscrasias.
Blood 02/2007; 109(4):1692-700. · 9.90 Impact Factor
