Scott J Rodig

Harvard Medical School, Boston, Massachusetts, United States

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Publications (142)1346.45 Total impact

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    ABSTRACT: The Ten-ElevenTranslocation-2 (TET2) gene encodes a member of the TET family of DNA methylcytosine oxidases that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) to initiate the demethylation of DNA within genomic CpG islands. Somatic loss-of-function mutations of TET2 are frequently observed in human myelodysplastic syndrome (MDS), which is a clonal malignancy characterized by dysplastic changes of developing blood cell progenitors leading to ineffective hematopoiesis. We used genome editing technology to disrupt the zebrafish Tet2 catalytic domain. tet2 m/m zebrafish exhibited normal embryonic and larval hematopoiesis, but developed progressive clonal myelodysplasia as they aged, culminating in MDS at 24 months of age, with dysplasia of myeloid progenitor cells and anemia with abnormal circulating erythrocytes. The resultant tet2 m/m mutant zebrafish lines show decreased levels of 5hmC in hematopoietic cells of the kidney marrow, but not in other cell types, most likely reflecting the ability of other Tet family members to provide this enzymatic activity in non-hematopoietic tissues but not in hematopoietic cells. tet2 m/m are viable and fertile, providing an ideal model to dissect altered pathways in hematopoietic cells and for small molecule screens in embryos to identify compounds with specific activity against tet2 mutant cells. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
    Molecular and cellular biology. 12/2014;
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    ABSTRACT: Activating mutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers, but oncogenic alterations in Gβ subunits have not been defined. Here we demonstrate that recurrent mutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as well as downstream effectors and disrupt Gα interactions with the Gβγ dimer. Different mutations in Gβ proteins clustered partly on the basis of lineage; for example, all 11 GNB1 K57 mutations were in myeloid neoplasms, and seven of eight GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 variants in Cdkn2a-deficient mouse bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K-mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, mutations in the gene encoding GNB1 co-occurred with oncogenic kinase alterations, including the BCR-ABL fusion protein, the V617F substitution in JAK2 and the V600K substitution in BRAF. Coexpression of patient-derived GNB1 variants with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 alterations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling.
    Nature medicine. 12/2014;
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    ABSTRACT: Background Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1-blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma. Methods In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression. Results Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling. Conclusions Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT01592370 .).
    New England Journal of Medicine 12/2014; · 54.42 Impact Factor
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    ABSTRACT: Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are aggressive tumors of mature B cells that are distinguished by a combination of histomorphological, phenotypic, and genetic features. A subset of B-cell lymphomas, however, has one or more characteristics that overlap BL and DLBCL, and are categorized as B-cell lymphoma unclassifiable, with features intermediate between BL and DLBCL (BCL-U). Molecular analyses support the concept that there is a biological continuum between BL and DLBCL that includes variable activity of MYC, an oncoprotein once thought to be only associated with BL, but now recognized as a major predictor of survival among patients with DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). We tested whether a targeted expression profiling panel could be used to categorize tumors as BL and DLBCL, resolve the molecular heterogeneity of BCL-U, and capture MYC activity using RNA from formalin-fixed, paraffin-embedded biopsy specimens. A diagnostic molecular classifier accurately predicted pathological diagnoses of BL and DLBCL, and provided more objective subclassification for a subset of BCL-U and genetic double-hit lymphomas as molecular BL or DLBCL. A molecular classifier of MYC activity correlated with MYC IHC and stratified patients with primary DLBCL treated with R-CHOP into high- and low-risk groups. These results establish a framework for classifying and stratifying MYC-driven, aggressive, B-cell lymphomas on the basis of quantitative molecular profiling that is applicable to fixed biopsy specimens. Copyright © 2014 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.
    The Journal of molecular diagnostics: JMD 11/2014; · 3.48 Impact Factor
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    ABSTRACT: Background Myc family members are important contributors to oncogenesis in a variety of tumors. Identification of therapeutic targets are needed in small cell lung carcinoma (SCLC), an aggressive disease with limited treatment options. Sequencing studies have identified MYC amplification in 2-7% of SCLC. We hypothesized that immunohistochemistry (IHC) will detect Myc protein overexpression in SCLC and will correlate with gene amplification.Design103 cases of formalin-fixed, paraffin-embedded SCLC were examined. Myc protein expression was scored based on extent of IHC staining. MYC copy number (CN) was evalutated using dual color chromogenic in situ hybridization (CISH) for the MYC locus and chromosome 8 (Chr8) centromeric control. Amplification was defined as a MYC/Chr8 ratio of 2 or greater.Results38% of SCLC had some degree of Myc protein expression and 9% of cases were MYC amplified. MYC CN was significantly correlated with extent of Myc protein expression (Spearman's ρ=0.57, p<0.01). There was no significant association between MYC expression or copy number and clinicopathologic features.ConclusionsMYC amplification by CISH was identified in 9% of SCLC and correlated with protein expression. As novel Myc-targeted therapies develop, CISH and IHC should be considered as biomarkers of Myc pathway dysregulation in SCLC.This article is protected by copyright. All rights reserved.
    Histopathology 11/2014; · 2.86 Impact Factor
  • Leukemia. 09/2014;
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    ABSTRACT: Activating mutations of the interleukin-7 receptor (IL7R) occur in approximately 10% of patients with T cell acute lymphoblastic leukaemia (T-ALL). Most mutations generate a cysteine at the transmembrane domain leading to receptor homodimerization through disulfide bond formation and ligand-independent activation of STAT5. We hypothesized that the reducing agent N-acetylcysteine (NAC), a well-tolerated drug used widely in clinical practice to treat acetaminophen overdose, would reduce disulfide bond formation, and inhibit mutant IL7R-mediated oncogenic signalling. We found that treatment with NAC disrupted IL7R homodimerization in IL7R-mutant DND-41 cells as assessed by non-reducing Western blot, as well as in a luciferase complementation assay. NAC led to STAT5 dephosphorylation and cell apoptosis at clinically achievable concentrations in DND-41 cells, and Ba/F3 cells transformed by an IL7R-mutant construct containing a cysteine insertion. The apoptotic effects of NAC could be rescued in part by a constitutively active allele of STAT5. Despite using doses lower than those tolerated in humans, NAC treatment significantly inhibited the progression of human DND-41 cells engrafted in immunodeficient mice. Thus, targeting leukaemogenic IL7R homodimerization with NAC offers a potentially effective and feasible therapeutic strategy that warrants testing in patients with T-ALL.
    British Journal of Haematology 09/2014; · 4.94 Impact Factor
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    ABSTRACT: Primary mediastinal (thymic) large B-cell lymphoma (PMBL) and diffuse large B-cell lymphoma (DLBCL) are tumors with distinct clinical and molecular characteristics that are difficult to distinguish by histopathologic and phenotypic analyses alone. Programmed cell death 1 ligand 2 (PD-L2) is a cell surface protein expressed by activated macrophages and dendritic cells that binds PD-1 on T cells to inhibit immune responses. Amplification and/or translocations involving chromosome 9p24.1, a region that includes PDCD1LG2-encoding PD-L2, is a common event in PMBL but not DLBCL and suggests that PD-L2 expression might be a distinguishing feature of PMBL. We developed an assay for the immunohistochemical detection of PD-L2 protein in fixed biopsy specimens (PD-L2 IHC), which we applied to a cohort of PMBLs and DLBCLs. For a subset of cases, we correlated the results of PD-L2 IHC with PDCD1LG2 copy number (CN) as determined by quantitative polymerase chain reaction. Twenty-three of 32 (72%) PMBLs but only 1 of 37 (3%) DLBCLs were positive by PD-L2 IHC. Among PMBLs with PDCD1LG2 CN gain, all were positive by PD-L2 IHC. One PMBL without CN gain was positive by PD-L2 IHC. When expressed in PMBL, PD-L2 was restricted to tumor cells and not detected on intratumoral macrophages. We conclude that PD-L2 protein is robustly expressed by the majority of PMBLs but only rare DLBCLs and often associated with PDCD1LG2 copy gain. PD-L2 IHC may serve as a useful ancillary test for distinguishing PMBL from DLBCL and for the rational selection of patients for therapeutic antibodies that inhibit PD-1 signaling.
    American Journal of Surgical Pathology 07/2014; · 4.87 Impact Factor
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    ABSTRACT: Intestinal intraepithelial T lymphocytes express the α E subunit of integrin αEβ7, which is detected by antibodies to CD103. Accordingly, within T-cell neoplasms, CD103 reactivity has most frequently been reported in enteropathy-associated T-cell lymphomas, which are postulated to arise from intestinal intraepithelial T lymphocytes. However, prior studies of CD103 expression in T-cell neoplasms have been limited by the requirement for fresh or frozen tissue, given the historic lack of an antibody to CD103 for use in paraffin-embedded sections. Thus, a thorough assessment of CD103 expression in a broad spectrum of T-cell neoplasms as categorized by the current classification system has not yet been performed. This study uses a newly described antibody to define the profile of CD103 immunoreactivity in paraffin sections of a wide variety of T-cell neoplasms (184 cases). Overall, 22 T-cell neoplasms (12%) were CD103 positive, including 7 of 15 gastrointestinal lymphomas (3.8% of total cases; 46% of gastrointestinal cases). In intestinal cases, CD103 positivity did not correlate with morphology, presence or absence of enteropathy, or immunohistochemical profile. A history of celiac disease was not documented in any case. Frequent but inconsistent reactivity was also noted for adult T-cell leukemia/lymphoma with 4 of 10 cases (40%) positive. In the remaining T-cell neoplasms representing most entities within the current World Health Organization classification, CD103 reactivity was sporadically observed in 11 of 159 cases (6.9%). CD103 positivity is an unusual feature in T-cell neoplasms and tends to occur in gastrointestinal lymphomas and adult T-cell leukemia/lymphoma but is not a consistent characteristic of these neoplasms.
    The American journal of surgical pathology. 07/2014;
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    ABSTRACT: Outcome for glioblastoma (GBM) remains dismal and innovative treatment strategies are desperately needed. Growing data support the contribution of local and systemic immune checkpoint molecules to regulating immunosuppression by GBM tumors.
    Neuro-oncology. 07/2014; 16 Suppl 3:iii11-iii12.
  • Cancer 07/2014; 120(13):1993-9. · 5.20 Impact Factor
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    ABSTRACT: CXCR4(WHIM) somatic mutations are common Waldenstrom's Macroglobulinemia (WM), and are associated with clinical resistance to ibrutinib. We engineered WM cells to express the most common WHIM (CXCR(S338X)) mutation in WM. Following SDF-1a stimulation, CXCR4(S338X) WM cells exhibited decreased receptor internalization; enhanced and sustained AKT and ERK signaling; decreased PARP and caspase 3 cleavage; and decreased Annexin V staining versus CXCR4 wild-type (WT) cells. CXCR4(S338X) related signaling and survival effects were blocked by the CXCR4 inhibitor AMD3100. SDF-1a treated CXCR4(S338X) WM cells showed sustained AKT and ERK activation and decreased apoptotic changes versus CXCR4(WT) cells following ibrutinib treatment, findings which were also reversed by AMD3100. AKT or ERK antagonists restored ibrutinib-triggered apoptotic changes in SDF-1a treated CXCR4(S338X) WM cells demonstrating their role SDF-1a mediated ibrutinib-resistance. Enhanced bone marrow pAKT staining was also evident in CXCR4(WHIM) versus CXCR4(WT) WM patients, and remained active despite ibrutinib therapy in CXCR4(WHIM) patients. Lastly, CXCR4(S338X) WM cells showed varying levels of resistance to other WM relevant therapeutics including bendamustine, fludarabine, bortezomib and idelalisib in the presence of SDF-1a. These studies demonstrate a functional role for CXCR4(WHIM) mutations, and provide a framework for investigation of CXCR4 inhibitors in WM.Leukemia accepted article preview online, 10 June 2014; doi:10.1038/leu.2014.187.
    Leukemia. 06/2014;
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    ABSTRACT: The myeloproliferative neoplasms primary myelofibrosis, polycythemia vera, and, rarely, essential thrombocythemia are characterized by variable degrees of bone marrow fibrosis, either at presentation or upon progression. The increasing use of emerging therapies that may alter disease biology and morphology demands accurate and reproducible assessment of fibrosis grade. To assess concordance of hematopoietic cellularity and fibrosis grading, three hematopathologists independently evaluated a total of 728 bone marrow biopsies from 261 patients with myeloproliferative neoplasms on three clinical trials using fedratinib (SAR302503), a JAK2 inhibitor, including 249 taken at baseline and 479 on therapy. Concordance between the pathologists was evaluated by Pearson correlation coefficient (cellularity) and unweighted kappa statistic (fibrosis grade). There was high correlation of cellularity assessment (r=0.92) and fibrosis grading (kappa=0.83) between the three pathologists. Concordance with World Health Organization (WHO) grade 3 samples was higher compared with grades 0, 1, and 2. Concordance of fibrosis grading in pretreatment samples was superior to that of post-treatment samples (kappa=0.83 and 0.79, respectively, P=0.023). Our analysis suggests that the updated 2008 WHO reticulin fibrosis grading system is highly reproducible, even in patients undergoing JAK2 inhibitor therapy. This system is practically applicable to establish baseline fibrosis grade as well as changes in fibrosis in subsequent samples on therapy.Modern Pathology advance online publication, 25 April 2014; doi:10.1038/modpathol.2014.69.
    Modern Pathology 04/2014; · 5.25 Impact Factor
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    ABSTRACT: Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) with four doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis (n = 1), hepatitis (n = 2), and uveitis (n = 2). On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8(+) and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7(+/-)/CD45RO(+) cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 instances of stable disease, and a disease-control rate of 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration. The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. These findings provide a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation, as well as future combinations of antiangiogenesis agents and immune checkpoint blockade. Cancer Immunol Res; 2(7); 1-11. ©2014 AACR.
    Cancer immunology research. 04/2014;
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    ABSTRACT: It has been recognized that monoclonal gammopathy of undetermined significance (MGUS) precedes a diagnosis of plasma cell myeloma in most patients. Recent gene expression array analysis has revealed that an MYC activation signature is detected in plasma cell myeloma but not in MGUS. In this study, we performed immunohistochemical studies using membrane CD138 and nuclear MYC double staining on bone marrow biopsies from patients who met the diagnostic criteria of plasma cell myeloma or MGUS. Our study demonstrated nuclear MYC expression in CD138-positive plasma cells in 22 of 26 (84%) plasma cell myeloma samples and in none of the 29 bone marrow samples from patients with MGUS. In addition, our data on the follow-up biopsies from plasma cell myeloma patients with high MYC expression demonstrated that evaluation of MYC expression in plasma cells can be useful in detecting residual disease. We also demonstrated that plasma cells gained MYC expression in 5 of 8 patients (62.5%) when progressing from MGUS to plasma cell myeloma. Analysis of additional lymphomas with plasmacytic differentiation, including lymphoplasmacytic lymphoma, marginal zone lymphoma, and plasmablastic lymphoma, reveals that MYC detection can be a useful tool in the diagnosis of plasma cell myeloma.
    The American journal of surgical pathology 04/2014; · 4.06 Impact Factor
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    ABSTRACT: Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, has been studied in multiple myeloma (MM) but lacks significant single agent activity. Based on preclinical studies showing synergistic activity of mTOR inhibitors with lenalidomide, we studied the combination of lenalidomide and everolimus in relapsed or refractory MM in a phase I clinical trial. We assessed patient samples using gene expression, Western blotting and immunohistochemistry to probe the mTOR pathway. Twenty-six patients were evaluable for toxicity. Dose-limiting toxicities included grade 4 neutropenia and thrombocytopenia. The maximum tolerated dose was lenalidomide 15 mg and everolimus 5 mg for 21 d with a 7 d rest period. Grade 3/4 adverse events included thrombocytopenia (35%) and neutropenia (42%). The overall response rate was 65% (1 complete response + 4 partial response + 10 minimal response). The median progression-free survival was 5·5 months and median overall survival was 29·5 months. Biomarker data demonstrated downregulation of phosphorylated p70S6K. Gene expression profiling suggested activation of mTOR in responders versus non-responders. The combination of lenalidomide and everolimus was well tolerated with predictable toxicities and showed responses in a heavily pretreated population. When confirmed with larger patient numbers, this analysis may guide patient selection for future clinical trials of mTOR inhibition in MM.
    British Journal of Haematology 04/2014; · 4.94 Impact Factor
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    ABSTRACT: The diagnosis of peripheral T-cell and NK-cell lymphomas (PTNKCL) is difficult with few standards for required ancillary studies. We evaluated a series of PTNKCLs using a tiered approach to immunohistochemistry and molecular genetic characterization to document diagnostic accuracy and clinical relevance. Seven hematopathologists reviewed 374 cases that included PTNKCL and non-PTNKCL cases to mimic diagnostic practice. Cases received tier 0, 1, and 2 diagnoses by 3 independent pathologists, on the basis of hematoxylin and eosin stains and progressive immunohistochemistry panels. A tier 2b diagnosis was rendered when gene rearrangement data were available, and a final consensus diagnosis was rendered after discussion of each case. Across all 374 cases, consensus agreement was 92.5%. For PTNKCLs, World Health Organization subclassification was possible in 16.5%, 37.1%, 82.8%, and 85.9% of individual reviewer diagnoses at tier 0, 1, 2, and 2b, respectively. Gene rearrangement contributed to a change in diagnosis in 51 of 647 (8%) individual reviews. Following this algorithm may provide prognostic information on the basis of individual marker expression in common PTNKCL types (CD4 in peripheral T-cell lymphoma, not otherwise specified and PD-1 in angioimmunoblastic T-cell lymphoma). This evidence-based approach to the diagnosis of PTNKCL informs practicing pathologists, clinical trial designers, and policy-makers regarding required ancillary studies.
    The American journal of surgical pathology 03/2014; · 4.06 Impact Factor
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    ABSTRACT: Classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (MLBCL) share similar histological, clinical and genetic features. In recent studies, we found that disease-specific chromosome 9p24.1/JAK2 amplification increased JAK2 expression and activity in both cHL and MLBCL. This prompted us to assess the activity of a clinical grade JAK2 selective inhibitor, fedratinib (SAR302503/TG101348), in in vitro and in vivo model systems of cHL and MLBCL with defined JAK2 copy numbers. We used functional and immunohistochemical analyses to investigate the preclinical activity of fedratinib and associated biomarkers in cell lines and murine xenograft models of cHL and MLBCL with known 9p24.1/JAK2 copy number. Chemical JAK2 inhibition decreased the cellular proliferation of cHL and MLBCL cell lines and induced their apoptosis. There was an inverse correlation between 9p24.1/JAK2 copy number and the EC50 of fedratinib. Chemical JAK2 inhibition decreased phosphorylation of JAK2, STAT1, STAT3 and STAT6 and reduced the expression of additional downstream targets, including PD-L1, in a copy number-dependent manner. In murine xenograft models of cHL and MLBCL with 9p24.1/JAK2 amplification, chemical JAK2 inhibition significantly decreased JAK2/STAT signaling and tumor growth and prolonged survival. In in vitro and in vivo studies, p-STAT3 was an excellent biomarker of baseline JAK2 activity and the efficacy of chemical JAK2 inhibition. In in vitro and in vivo analyses, cHL and MLBCL with 9p24.1/JAK2 copy gain are sensitive to chemical JAK2 inhibition suggesting that clinical evaluation of JAK2 blockade is warranted.
    Clinical Cancer Research 03/2014; · 7.84 Impact Factor
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    ABSTRACT: The NPM-ALK fusion protein is found in ALK(+) anaplastic large cell lymphomas harboring the t(2;5) chromosomal translocation. Patients harboring ALK translocations typically have an excellent prognosis with conventional chemotherapy and a reported 5-year survival rate of 70%. Although most patients with ALK(+) anaplastic large cell lymphoma have a good prognosis, some patients do not respond to standard therapies. In patients with refractory anaplastic large cell lymphoma who can achieve remission, allogeneic stem cell transplant is a potentially curative option. This article describes a patient with refractory ALK(+) anaplastic large cell lymphoma who experienced a complete response to the ALK inhibitor crizotinib and then underwent an allogeneic stem cell transplant followed by crizotinib maintenance therapy.
    Journal of the National Comprehensive Cancer Network: JNCCN 03/2014; 12(3):323-6. · 5.11 Impact Factor
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    ABSTRACT: Accurate classification is essential for understanding the pathophysiology of a disease and can inform therapeutic choices. For hematopoietic malignancies, a classification scheme based on the phenotypic similarity between tumor cells and normal cells has been successfully used to define tumor subtypes; however, use of normal cell types as a reference by which to classify solid tumors has not been widely emulated, in part due to more limited understanding of epithelial cell differentiation compared with hematopoiesis. To provide a better definition of the subtypes of epithelial cells comprising the breast epithelium, we performed a systematic analysis of a large set of breast epithelial markers in more than 15,000 normal breast cells, which identified 11 differentiation states for normal luminal cells. We then applied information from this analysis to classify human breast tumors based on normal cell types into 4 major subtypes, HR0-HR3, which were differentiated by vitamin D, androgen, and estrogen hormone receptor (HR) expression. Examination of 3,157 human breast tumors revealed that these HR subtypes were distinct from the current classification scheme, which is based on estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Patient outcomes were best when tumors expressed all 3 hormone receptors (subtype HR3) and worst when they expressed none of the receptors (subtype HR0). Together, these data provide an ontological classification scheme associated with patient survival differences and provides actionable insights for treating breast tumors.
    The Journal of clinical investigation 01/2014; · 15.39 Impact Factor

Publication Stats

4k Citations
1,346.45 Total Impact Points

Institutions

  • 2012–2014
    • Harvard Medical School
      Boston, Massachusetts, United States
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
    • Weill Cornell Medical College
      • Division of Hospital Medicine
      New York City, New York, United States
  • 2005–2014
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, Massachusetts, United States
  • 2003–2014
    • Brigham and Women's Hospital
      • • Department of Pathology
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 2011–2012
    • The University of Manchester
      • Faculty of Medical and Human Sciences
      Manchester, ENG, United Kingdom
  • 2010–2012
    • Massachusetts General Hospital
      • Department of Pathology
      Boston, Massachusetts, United States
  • 2009
    • Boston Children's Hospital
      Boston, Massachusetts, United States