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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EUnderstanding the pathophysiologic basis of lymphomas and the contribution of molecular and cellular features to their natural history is enabling identification of therapeutic targets. Drugs that hit some of these targets have already produced impressive responses in various lymphoma subsets.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Epathogenesis\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Elymphoid malignancy\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Enext-generation sequencing\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Egenetics\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHodgkin lymphoma\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EThe Presidential Symposium explored the rapidly evolving understanding of the pathogenesis of lymphoid malignancies and how this knowledge will enable the identification of therapeutic targets.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003ERandy Gascoyne, MD, British Columbia Cancer Agency, Vancouver, British Columbia, Canada, provided a review of next-generation sequencing, which has both enhanced understanding of the genomic basis of non-Hodgkin lymphoma (NHL) and translated into specific, targeted therapies for patients.\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003ENext-generation sequencing technologies, such as whole genome sequencing and RNA sequencing, are being used to search for somatic mutations, chromosomal alterations (eg, translocations), and gene expression changes in NHL tumors. Next-generation sequencing has identified several recurrent mutations in indolent B-cell NHL, aggressive B-cell NHLs, and classic Hodgkin lymphoma (cHL).\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EDr Gascoyne highlighted the strength of sequencing a single cell line, extending it into sequencing of clinical samples, which led to identifying a genetic alteration (translocation of CIITA) integral to primary mediastinal B-cell lymphoma (PMBCL) [Steidl C et al. \u003Cem\u003ENature.\u003C\/em\u003E 2011]. Translocation of CIITA is a common genetic alteration shared between cHL and PMBCL. A search for fusion partners of CIITA uncovered the ligands of programmed death 1 (PD-1)\u2014PD-L1 and PD-L2\u2014which, when overexpressed, can induce T-cell anergy in the microenvironment, referred to as an immunologic \u201cdouble whammy,\u201d he said.\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EGenetic aberrations of the PD-L1\/2 locus are present across the spectrum of B-cell lymphoid malignancies. PD-L1\/2 amplification and rearrangement are significantly correlated with transcript expression [Twa DD et al. \u003Cem\u003EBlood.\u003C\/em\u003E 2014]. Given the function of PD-Ls in repressing the antitumor response, cases harboring a translocation or high-level amplification of the PD-1 ligands are compelling candidates for nivolumab therapy, said Dr Gascoyne.\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EThe power of next-generation sequencing can be harnessed to finding targeted agents, as in the case of EZH2. Somatic mutations altering EZH2 were first found in follicular and diffuse large B-cell lymphomas of germinal-center origin in 2010 [Morin RD et al. \u003Cem\u003ENat Gen.\u003C\/em\u003E 2010]. Mutations in EZH2 represent a gain-of-function mutation. EZH2 inhibition has been found to kill mutant lymphoma cells [Knutson SK et al. \u003Cem\u003ENat Chem Biol.\u003C\/em\u003E 2012] and therefore may be a therapeutic strategy in some NHLs.\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EMargaret Shipp, MD, Harvard Medical School, Boston, Massachusetts, USA, discussed emerging insights into the genetic bases for immune escape in lymphoid malignancies and promising associated treatment strategies.\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EExpression of the PD-1 ligands on tumor cells allows tumor cells to engage the PD-1 receptor on T cells, and activation of PD-1 signaling generates a cascade that results in a reduced activation signal and a phenotype called T-cell exhaustion [Freeman GJ et al. \u003Cem\u003EJ Exp Med.\u003C\/em\u003E 2000], which can be reversed by PD-1 blockade, she explained.\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EPreviously, Dr Shipp\u2019s group found a recurrent alteration at chromosome 9p24.1 in primary cHL and PMBCL. Two of the genes that were most closely associated with 9p24.1 amplification were the 2 ligands of PD-1\u2014PD-L1 and PD-L2 [Green MR et al. \u003Cem\u003EBlood.\u003C\/em\u003E 2010]. High copy numbers of 9p24.1 correlate with increased expression of the PD-1 ligands due to gene amplification and increased expression of the JAK2 protein and associated JAK-STAT signaling [Green MR et al. \u003Cem\u003EBlood.\u003C\/em\u003E 2010; Hao Y et al. \u003Cem\u003EClin Cancer Res.\u003C\/em\u003E 2014].\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EEpstein-Barr virus (EBV) infection is an additional mechanism of PD-L1 induction, said Dr Shipp. PD-L1 has been detected in a majority of EBV-positive posttransplant lymphoproliferative disorders (PTLDs), and cHL and EBV-positive PTLD use complementary mechanisms to upregulate PD-L1 in tumor cells [Green MR et al. \u003Cem\u003EClin Cancer Res.\u003C\/em\u003E 2012; Chen B et al. \u003Cem\u003EClin Cancer Res.\u003C\/em\u003E 2013].\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EThe genetic bases for overexpression of the PD-1 ligands in Hodgkin lymphoma led Dr Shipp and her colleagues to evaluate the efficacy of PD-1 blockade in this disease. T-cell reactivation through PD-1 blockade, using the nivolumab antibody, induced long-lasting responses in 87% of patients with relapsed\/refractory Hodgkin lymphoma [Armand P et al. ASH 2014 (abst 289); Ansell SM et al. \u003Cem\u003EN Engl J Med.\u003C\/em\u003E 2014]. An additional PD-1 blocking antibody, pembrolizumab, was also effective in heavily pretreated cHL in an early-phase clinical trial [Moskowitz CH et al. ASH 2014 (abstr 290)].\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EPD-1 blockade with nivolumab is also being evaluated in additional lymphoid malignancies including follicular lymphoma, diffuse large B-cell lymphoma, and T-cell lymphoma [Lesokhin AM et al. ASH 2014 (abstr 291)]. In these lymphoid malignancies, emerging insights regarding biological bases for PD-1 ligand overexpression may help identify patients who are most likely to benefit from PD-1 blockade [Monti S et al. \u003Cem\u003EBlood.\u003C\/em\u003E 2005; Chen B et al. \u003Cem\u003EClin Cancer Res.\u003C\/em\u003E 2013; Chapuy B et al. ASH 2014 (abst 74)].\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003ERalf K\u00fcppers, PhD, University of Duisburg-Essen, Essen, Germany, provided new insights into the biology and microenvironment of Hodgkin lymphoma. The tumor cells in cHL are called Hodgkin and Reed-Sternberg (HRS) cells. The HRS tumor cells of cHL and the lymphocyte-predominant tumor cells of nodular lymphocyte\u2013predominant Hodgkin lymphoma are both derived from germinal center B cells. HRS cells are generated from \u201ccrippled\u201d germinal center B cells, losing nearly all of their B cell\u2013specific gene expression program. Multiple factors contribute to lost B-cell marker expression, including downregulation of key B-cell transcription factors, aberrant expression of master regulators of non\u2013B cells, and epigenetic silencing of B-cell genes [Schwering I et al. \u003Cem\u003EBlood.\u003C\/em\u003E 2003; Tiacci E et al. \u003Cem\u003EBlood.\u003C\/em\u003E 2012]. Reexpression of the B-cell program is toxic for HRS cells. The loss of the B-cell phenotype is presumably a critical pathogenetic event in Hodgkin lymphoma, as it is required for HRS precursor cells to escape from apoptosis as crippled germinal center B cells.\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003EThe genetic lesions involved in the pathogenesis of Hodgkin lymphoma are not fully known, but numerous members and regulators of the NF-\u03baB and JAK-STAT signaling pathways are affected, suggesting an important role for these pathways in the pathogenesis of the disease. Some genetic lesions involve epigenetic regulators, and evidence has emerged that HRS cells have undergone extensive epigenetic alterations compared with normal B cells.\u003C\/p\u003E\n         \u003Cp id=\u0022p-16\u0022\u003EHRS cells represent \u0026lt;\u20091% of cells in lymphoma tissue. The Hodgkin lymphoma microenvironment is a mixed infiltrate of various immune cells, with T cells being the largest cell population. Reed-Sternberg cell interactions with T cells in the microenvironment are likely critical for Hodgkin lymphoma pathophysiology [K\u00fcppers R. \u003Cem\u003ENat Rev Cancer.\u003C\/em\u003E 2009].\u003C\/p\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EComposite lymphomas are rare combinations of 2 histopathologically distinct lymphomas in the same patient, often a Hodgkin lymphoma and an NHL, or 2 NHLs. Composite lymphomas are frequently clonally related and carry somatically mutated immunoglobulin variable genes with both shared and distinct mutations, which offers a strong argument that both lymphomas derive from a common precursor: a mature germinal center B cell. Initial mutation studies validate a multistep transformation process for such lymphomas.\u003C\/p\u003E\n         \u003Cp id=\u0022p-18\u0022\u003EProf K\u00fcppers showed results from long-term time-lapse microscopy Hodgkin lymphoma cell lines that demonstrate that refusion is a major route of Reed-Sternberg cell generation from Hodgkin cells [Rengstl B et al. \u003Cem\u003EPNAS\u003C\/em\u003E. 2014]. This refusion is mostly, if not always, based on incomplete cytokinesis, but the mechanism for failure to complete cytokinesis is unknown. A striking downregulation of many genes involved in regulation of mitosis, cytokinesis, genetic stability, and DNA repair in HRS cells indicates a potential role for genomic instability in Reed-Sternberg cell generation.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 SAGE Publications\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/55\/26.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzoagd\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}