John D Shaughnessy

Yale University, New Haven, Connecticut, United States

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Publications (220)1854.36 Total impact

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    ABSTRACT: Secreted protein CCN1, encoded by CYR61, is involved in wound healing, angiogenesis, and osteoblast differentiation. We identified CCN1 as a microenvironmental factor produced by mesenchymal cells and overexpressed in bones of a subset of patients with monoclonal gammopathy of undetermined significance (MGUS), asymptomatic myeloma (AMM), and multiple myeloma (MM). Our analysis showed that overexpression of CYR61 was independently associated with superior overall survival of MM patients enrolled in our Total Therapy 3 protocol. Moreover, elevated CCN1 was associated with longer time for MGUS/AMM to progress to overt MM. During remission from MM, high levels of CCN1 were associated with superior progression-free and overall survival and stratified patients with molecularly defined high-risk MM. Recombinant CCN1 directly inhibited in vitro growth of MM cells, and overexpression of CYR61 in MM cells reduced tumor growth and prevented bone destruction in vivo in SCID-hu mice. Signaling through αvβ3 was required for CCN1 prevention of bone disease. CYR61 expression may signify early perturbation of the microenvironment before conversion to overt MM and may be a compensatory mechanism to control MM progression. Therapeutics that upregulate CYR61 should be investigated for treating MM bone disease.
    Blood 07/2014; · 9.78 Impact Factor
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    ABSTRACT: Widespread adoption of genomic technologies in the management of heterogeneous indications, including Multiple Myeloma, has been hindered by concern over variation between published gene expression signatures, difficulty in physician interpretation and the challenge of obtaining sufficient genetic material from limited patient specimens.
    BMC Medical Genomics 05/2014; 7(1):25. · 3.47 Impact Factor
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    ABSTRACT: All cases of clinical myeloma (CMM) are preceded by an asymptomatic monoclonal gammopathy (AMG), classified as either monoclonal gammopathy of undetermined significance (MGUS) or asymptomatic multiple myeloma (AMM). We analyzed data from AMG patients (n=331) enrolled in a prospective observational clinical trial (S0120). Baseline data from clinical variables, gene expression profiles (GEP) of purified tumor cells, and findings of magnetic resonance imaging (MRI) were correlated with the risk of progression to CMM requiring therapy. GEP of purified tumor cells revealed that all molecular subtypes of CMM are also represented in the AMG phase. An increased risk score (>-0.26) (based on a 70-gene signature, GEP70) was an independent predictor of the risk of progression to CMM. Combination of elevated serum free light chain, M-spike and GEP70 risk score identified a subset with high risk (67% at 2 years) of progression to CMM requiring therapy. Importantly, absence of these factors in AMM patients predicted low-risk similar to MGUS. Detection of multiple (>1) focal lesions by MRI also conferred an increased risk of progression. These data demonstrate that signatures associated with high-risk CMM impact disease risk and support inclusion of genomic analysis in the clinical management of AMGs. This study is registered at ClinicalTrials.gov, identifier: NCT00900263.
    Blood 10/2013; · 9.78 Impact Factor
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    ABSTRACT: Multiple myeloma (MM) is an incurable neoplasm caused by proliferation of malignant plasma cells in the bone marrow (BM). MM is characterized frequently by a complete or partial deletion of chromosome 13q14, seen in more than 50% of patients at diagnosis. Within this deleted region the tripartite motif containing 13 (TRIM13, also termed RFP2) gene product has been proposed to be a tumour suppressor gene (TSG). Here, we show that low expression levels of TRIM13 in MM are associated with chromosome 13q deletion and poor clinical outcome. We present a functional analysis of TRIM13 using a loss-of-function approach, and demonstrate that TRIM13 downregulation decreases tumour cell survival as well as cell cycle progression and proliferation of MM cells. In addition, we provide evidence for the involvement of TRIM13 downregulation in inhibiting the NF kappa B pathway and the activity of the 20S proteasome. Although this data does not support a role of TRIM13 as a TSG, it substantiates important roles of TRIM13 in MM tumour survival and proliferation, underscoring its potential role as a novel target for therapeutic intervention.
    British Journal of Haematology 05/2013; · 4.94 Impact Factor
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    ABSTRACT: Myeloma cells typically grow in bone, recruit osteoclast precursors and induce their differentiation and activity in areas adjacent to tumor foci. Bruton's tyrosine kinase (BTK), of the TEC family, is expressed in hematopoietic cells and is particularly involved in B-lymphocyte function and osteoclastogenesis. We demonstrated BTK expression in clinical myeloma plasma cells, interleukin (IL)-6- or stroma-dependent cell lines and osteoclasts. SDF-1 induced BTK activation in myeloma cells and BTK inhibition by small hairpin RNA or the small molecule inhibitor, LFM-A13, reduced their migration toward stromal cell-derived factor-1 (SDF-1). Pretreatment with LFM-A13 also reduced in vivo homing of myeloma cells to bone using bioluminescence imaging in the SCID-rab model. Enforced expression of BTK in myeloma cell line enhanced cell migration toward SDF-1 but had no effect on short-term growth. BTK expression was correlated with cell-surface CXCR4 expression in myeloma cells (n=33, r=0.81, p<0.0001), and BTK gene and protein expression was more profound in cell-surface CXCR4-expressing myeloma cells. BTK was not upregulated by IL-6 while its inhibition had no effect on IL-6 signaling in myeloma cells. Human osteoclast precursors also expressed BTK and cell-surface CXCR4 and migrated toward SDF-1. LFM-A13 suppressed migration and differentiation of osteoclast precursors as well as bone-resorbing activity of mature osteoclasts. In primary myeloma-bearing SCID-rab mice, LFM-A13 inhibited osteoclast activity, prevented myeloma-induced bone resorption and moderately suppressed myeloma growth. These data demonstrate BTK and cell-surface CXCR4 association in myeloma cells and that BTK plays a role in myeloma cell homing to bone and myeloma-induced bone disease. Am. J. Hematol., 2013. © 2013 Wiley Periodicals, Inc.
    American Journal of Hematology 03/2013; · 4.00 Impact Factor
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    ABSTRACT: Multicentric Castleman Disease is largely driven by increased signaling in the pathway for the plasma cell growth factor interleukin-6. We hypothesized that interleukin-6/interleukin-6 receptor/gp130 polymorphisms contribute to increased interleukin-6 and/or other components of the interleukin-6 signaling pathway in HIV-negative Castleman Disease patients. The study group was composed of 58 patients and 50 healthy donors of a similar racial/ethnic profile. Of seven polymorphisms chosen for analysis, we observed an increased frequency between patients and controls of the minor allele of interleukin-6 receptor polymorphism rs4537545, which is in linkage disequilibrium with interleukin-6 receptor polymorphism rs2228145. Further, individuals possessing at least one copy of the minor allele of either polymorphism expressed higher levels of soluble interleukin-6 receptor. These elevated interleukin-6 receptor levels may contribute to increased interleukin-6 activity through the trans-signaling pathway. These data suggest that interleukin-6 receptor polymorphism may be a contributing factor in Castleman Disease, and further research is warranted.
    PLoS ONE 01/2013; 8(1):e54610. · 3.73 Impact Factor
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    ABSTRACT: PURPOSE: It is highly challenging to develop reliable diagnostic tests to predict patients' responsiveness to anticancer treatments on clinical endpoints before commencing the definitive phase III randomized trial. Development and validation of genomic signatures in the randomized trial can be a promising solution. Such signatures are required to predict quantitatively the underlying heterogeneity in the magnitude of treatment effects.EXPERIMENTAL DESIGN: We propose a framework for developing and validating genomic signatures in randomized trials. Codevelopment of predictive and prognostic signatures can allow prediction of patient-level survival curves as basic diagnostic tools for treating individual patients.RESULTS: We applied our framework to gene-expression microarray data from a large-scale randomized trial to determine whether the addition of thalidomide improves survival for patients with multiple myeloma. The results indicated that approximately half of the patients were responsive to thalidomide, and the average improvement in survival for the responsive patients was statistically significant. Cross-validated patient-level survival curves were developed to predict survival distributions of individual future patients as a function of whether or not they are treated with thalidomide and with regard to their baseline prognostic and predictive signature indices.CONCLUSION: The proposed framework represents an important step toward reliable predictive medicine. It provides an internally validated mechanism for using randomized clinical trials to assess treatment efficacy for a patient population in a manner that takes into consideration the heterogeneity in patients' responsiveness to treatment. It also provides cross-validated patient-level survival curves that can be used for selecting treatments for future patients. Clin Cancer Res; 18(21); 1-9. ©2012 AACR.
    Clinical Cancer Research 08/2012; · 7.84 Impact Factor
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    ABSTRACT: Because dexamethasone remains a key component of myeloma therapy, we wished to examine the impact of baseline and relapse expression levels of the glucocorticoid receptor gene NR3C1 on survival outcomes in the context of treatment with or without thalidomide. We investigated the clinical impact of gene expression profiling (GEP)-derived expression levels of NR3C1 in 351 patients with GEP data available at baseline and in 130 with data available at relapse, among 668 subjects accrued to total therapy 2 (TT2). Low NR3C1 expression levels had a negative impact on progression-free survival (PFS; HR, 1.47; P = 0.030) and overall survival (OS; HR, 1.90; P = 0.002) in the no-thalidomide arm. Conversely, there was a significant clinical benefit of thalidomide for patients with low receptor levels (OS: HR, 0.54; P = 0.015; PFS: HR, 0.54; P = 0.004), mediated most likely by thalidomide's upregulation of NR3C1. In the context of both baseline and relapse parameters, post-relapse survival (PRS) was adversely affected by low NR3C1 levels at relapse in a multivariate analysis (HR, 2.61; P = 0.012). These findings justify the inclusion of NR3C1 expression data in the work-up of patients with myeloma as it can significantly influence the choice of therapy and, ultimately, OS. The identification of an interaction term between thalidomide and NR3C1 underscores the importance of pharmacogenomic studies in the systematic study of new drugs. Clin Cancer Res; 18(19); 5499-506. ©2012 AACR.
    Clinical Cancer Research 08/2012; 18(19):5499-506. · 7.84 Impact Factor
  • Christoph J Heuck, John D Shaughnessy
    Seminars in Hematology 07/2012; 49(3):193-5. · 3.36 Impact Factor
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    ABSTRACT: Bone disease in patients with multiple myeloma (MM) is characterized by increase in the numbers and activity of bone-resorpting osteoclasts and decrease in the number and function of bone-formation osteoblasts. MM-triggered inhibition of bone formation may stem from suppression of Wnt/β-catenin signaling, a pivotal pathway in the differentiation of mesenchymal stem cells (MSC) into osteoblasts, and regulating production of receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) axis by osteoblasts. Proteasome inhibitors (PIs), such as bortezomib (Bz), induce activation of Wnt/β-catenin pathway and MSC differentiation toward osteoblasts. PIs also suppress osteoclastogenesis, possibly through regulating multiple pathways including NF-κB, Bim, and the ratio of RANKL/OPG. The critical role of PI in increasing osteoblast function and suppression of osteoclast activity is highlighted by clinical evidence of increases in bone formation and decreases in bone resorption makers. This review will discuss the function of PIs in stimulating bone formation and suppression of bone resorption, and the mechanism underlying this process that leads to inhibition bone disease in MM patients.
    Seminars in Hematology 07/2012; 49(3):243-8. · 3.36 Impact Factor
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    ABSTRACT: To determine whether primary plasma cell leukemia (PPCL) remains a high-risk multiple myeloma feature in the context of contemporary therapy and gene-expression profiling (GEP), we reviewed records of 1474 patients with myeloma, who were enrolled in Total Therapy protocols or treated identically off protocol. A total of 27 patients (1.8%) were classified as having PPCL. As a group, these patients more often had low hemoglobin, high beta-2-microglobulin, high lactate dehydrogenase, low albumin and cytogenetic abnormalities. Among 866 patients with GEP results, the PPCL group more often had disease that was classified as high risk, and in CD-1 and MF molecular subgroups. Regardless of the therapeutic protocol, patients with PPCL had shorter median overall survival (OS; 1.8 years), progression-free survival (PFS; 0.8 years) and complete response duration (CRD; 1.3 years) than the remainder, whose clinical outcomes had improved markedly with successive protocols. Multivariate analyses of pretreatment parameters showed that PPCL was a highly significant independent adverse feature linked to OS, PFS and CRD. In GEP analyses, 203 gene probes distinguished PPCL from non-PPCL; the identified genes were involved in the LXR/RXR activation, inositol metabolism, hepatic fibrosis/hepatic stellate-cell activation and lipopolysaccharide/interleukin-1-mediated inhibition of RXR function pathways. Different treatment approaches building on these genomic differences may improve the grave outcome of patients with PPCL.Leukemia advance online publication, 18 May 2012; doi:10.1038/leu.2012.107.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2012; · 10.16 Impact Factor
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    ABSTRACT: Cytogenetic abnormalities are important clinical parameters in various types of cancer, including multiple myeloma. We developed a model to predict cytogenetic abnormalities in patients with multiple myeloma using gene expression profiling and validated it by different cytogenetic techniques. The model has an accuracy rate up to 0.89. These results provide proof of concept for the hypothesis that gene expression profiling is a superior genomic method for clinical molecular diagnosis and/or prognosis.
    Blood 04/2012; 119(21):e148-50. · 9.78 Impact Factor
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    ABSTRACT: Background Patients with gene expression profiling-defined high-risk myeloma in relapse have poor outcomes with current therapies. We tested whether natural killer cells expanded by co-culture with K562 cells transfected with 41BBL and membrane-bound interleukin-15 could kill myeloma cells with a high-risk gene expression profile in vitro and in a unique model which recapitulates human myeloma. DESIGN AND METHODS: OPM2 and high-risk primary myeloma tumors were grown in human fetal bone implanted into non-obese diabetic severe combined immunodeficiency mice with a deficient interleukin-2 receptor gamma chain. These mice are devoid of endogenous natural killer and T-cell activity and were used to determine whether adoptively transferred expanded natural killer cells could inhibit myeloma growth and myeloma-associated bone destruction. RESULTS: Natural killer cells from healthy donors and myeloma patients expanded a median of 804- and 351-fold, respectively, without significant T-cell expansion. Expanded natural killer cells killed both allogeneic and autologous primary myeloma cells avidly via a perforin-mediated mechanism in which the activating receptor NKG2D, natural cytotoxicity receptors, and DNAX-accessory molecule-1 played a central role. Adoptive transfer of expanded natural killer cells inhibited the growth of established OPM2 and high-risk primary myeloma tumors grown in the murine model. The transferred, expanded natural killer cells proliferated in vivo in an interleukin-2 dose-dependent fashion, persisted up to 4 weeks, were readily detectable in the human bone, inhibited myeloma growth and protected bone from myeloma-induced osteolysis. Conclusions These studies provide the rationale for testing expanded natural killer cells in humans.
    Haematologica 03/2012; 97(9):1348-56. · 5.94 Impact Factor
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    ABSTRACT: The membrane glycoprotein MRC OX-2 (CD200) is expressed in several lymphoid malignancies. However, the diagnostic usefulness and potential prognostic importance of CD200 expression have not been rigorously examined. We show that CD200 is uniformly expressed in chronic lymphocytic leukemia (CLL) and absent in mantle cell lymphoma (MCL). It is important to note that expression of CD200 is retained even in CLLs with immunophenotypic aberrancies, making CD200 a particularly useful marker for discrimination between these cases and MCL. CD200 is expressed in nearly all precursor B-lymphoblastic leukemias, with aberrant overexpression or underexpression compared with normal B-cell progenitors in 55% of cases. More than 70% of plasma cell myelomas (PCMs) expressed CD200, and loss of CD200 expression in PCM may be associated with more clinically aggressive disease. CD200 is expressed in several hematolymphoid neoplasms. Analysis of its expression has several diagnostic and potentially prognostic applications in the flow cytometric evaluation of lymphoid malignancies.
    American Journal of Clinical Pathology 01/2012; 137(1):93-100. · 2.88 Impact Factor
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    ABSTRACT: Microarray data have been used for gene signature selection to predict clinical outcomes. Many studies have attempted to identify factors that affect models' performance with only little success. Fine-tuning of model parameters and optimizing each step of the modeling process often results in over-fitting problems without improving performance. We propose a quantitative measurement, termed consistency degree, to detect the correlation between disease endpoint and gene expression profile. Different endpoints were shown to have different consistency degrees to gene expression profiles. The validity of this measurement to estimate the consistency was tested with significance at a p-value less than 2.2e-16 for all of the studied endpoints. According to the consistency degree score, overall survival milestone outcome of multiple myeloma was proposed to extend from 730 days to 1561 days, which is more consistent with gene expression profile. For various clinical endpoints, the maximum predictive powers of different microarray-based models are limited by the correlation between endpoint and gene expression profile of disease samples as indicated by the consistency degree score. In addition, previous defined clinical outcomes can also be reassessed and refined more coherent according to related disease gene expression profile. Our findings point to an entirely new direction for assessing the microarray-based predictive models and provide important information to gene signature based clinical applications.
    BMC Genomics 12/2011; 12 Suppl 5:S3. · 4.40 Impact Factor
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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. · 9.78 Impact Factor
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    Shweta S Chavan, John D Shaughnessy, Ricky D Edmondson
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    ABSTRACT: Many primary biological databases are dedicated to providing annotation for a specific type of biological molecule such as a clone, transcript, gene or protein, but often with limited cross-references. Therefore, enhanced mapping is required between these databases to facilitate the correlation of independent experimental datasets. For example, molecular biology experiments conducted on samples (DNA, mRNA or protein) often yield more than one type of 'omics' dataset as an object for analysis (eg a sample can have a genomics as well as proteomics expression dataset available for analysis). Thus, in order to map the two datasets, the identifier type from one dataset is required to be linked to another dataset, so preventing loss of critical information in downstream analysis. This identifier mapping can be performed using identifier converter software relevant to the query and target identifier databases. This review presents the publicly available web-based biological database identifier converters, with comparison of their usage, input and output formats, and the types of available query and target database identifier types.
    Human genomics 10/2011; 5(6):703-8.
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    ABSTRACT: Despite improvement in therapeutic efficacy, multiple myeloma (MM) remains incurable with a median survival of approximately 10 years. Gene-expression profiling (GEP) can be used to elucidate the molecular basis for resistance to chemotherapy through global assessment of molecular alterations that exist at diagnosis, after therapeutic treatment and that evolve during tumor progression. Unique GEP signatures associated with recurrent chromosomal translocations and ploidy changes have defined molecular classes with differing clinical features and outcomes. When compared to other stratification systems the GEP70 test remained a significant predictor of outcome, reduced the number of patients classified with a poor prognosis, and identified patients at increased risk of relapse despite their standard clinico-pathologic and genetic findings. GEP studies of serial samples showed that risk increases over time, with relapsed disease showing GEP shifts toward a signature of poor outcomes. GEP signatures of myeloma cells after therapy were prognostic for event-free and overall survival and thus may be used to identify novel strategies for overcoming drug resistance. This brief review will focus on the use of GEP of MM to define high-risk myeloma, and elucidate underlying mechanisms that are beginning to change clinical decision-making and inform drug design.
    International journal of hematology 10/2011; 94(4):321-33. · 1.17 Impact Factor
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    ABSTRACT: It was demonstrated that metallopanstimulin-1 (MPS-1, RPS27) inhibited the growth of tumors formed by head and neck squamous cell carcinoma cells and reduced paxillin gene expression. The present study examined whether and how MPS-1 affects another type of cancer, multiple myeloma (CAG). Enhanced expression of MPS-1 dramatically inhibited CAG in vitro and in vivo. Overexpression of MPS-1 resulted in decreased fibroblast growth factor (FGF2) receptor 3 and impaired endogenous MAPK/ErK signaling. MAPK/ErK signaling was not stimulated by adding recombinant FGF2 to myeloma cells overexpressing MPS-1. These data suggest that MPS-1 suppresses CAG growth and that weakened FGF2 signaling may contribute to this effect.
    Clinical lymphoma, myeloma & leukemia 09/2011; 11(6):490-7.

Publication Stats

11k Citations
1,854.36 Total Impact Points

Institutions

  • 2013
    • Yale University
      • Yale Cancer Center
      New Haven, Connecticut, United States
    • Signal Genetics
      New York City, New York, United States
  • 1999–2013
    • University of Arkansas for Medical Sciences
      • Department of Emergency Medical Sciences
      Little Rock, Arkansas, United States
    • University of Arkansas at Little Rock
      Little Rock, Arkansas, United States
  • 2009
    • University of Arkansas
      Fayetteville, Arkansas, United States
  • 2007–2009
    • Cancer Research and Biostatistics
      Seattle, Washington, United States
    • University of Alabama at Birmingham
      • Department of Pathology
      Birmingham, AL, United States
    • SickKids
      • Centre of Applied Genomics (TCAG)
      Toronto, Ontario, Canada
  • 2008
    • Kyoto University
      • Department of Public Health
      Kyoto, Kyoto-fu, Japan
    • The Ohio State University
      • Department of Internal Medicine
      Columbus, OH, United States
  • 1993–2007
    • National Institutes of Health
      • • Laboratory of Cancer Biology and Genetics
      • • Laboratory of Molecular Pharmacology
      • • Laboratory of Genetics (LG)
      Bethesda, MD, United States
  • 2005–2006
    • University of Maryland, Baltimore
      • Greenebaum Cancer Center
      Baltimore, Maryland, United States
    • Mayo Foundation for Medical Education and Research
      • Division of Hematology
      Rochester, Michigan, United States
  • 2004
    • Queen's University Belfast
      • Centre for Cancer Research and Cell Biology
      Belfast, NIR, United Kingdom
  • 1990–1994
    • National Cancer Institute (USA)
      • Laboratory of Population Genetics
      Maryland, United States
  • 1989
    • NCI-Frederick
      Maryland, United States