Prediction of Survival in Follicular Lymphoma Based on Molecular Features of Tumor-Infiltrating Immune Cells

Davé, Sandeep S.; Wright, George W.; Tan, Bruce K.; Rosenwald, Andreas; Gascoyne, Randy D.; Chan, Wing C.; Fisher, Richard I.; Braziel, Rita M.; Rimsza, Lisa M.; Grogan, Thomas M.; Miller, Thomas P.; LeBlanc, Michael; Greiner, Timothy C.; Weisenburger, Dennis D.; Lynch, James C.; Vose, Julie M.; Armitage, Jamés O.; Smeland, Erlend B.; Kvaløy, Stein; Holte, Harald; Delabie, Jan; Connors, Joseph M.; Lansdorp, Peter M.; Ouyang, Qing; Lister, T. A.; Davies, Andrew; Norton, A. J.; Müller-Hermelink, H. K.; Ott, German; Campo, Elı́as; Montserrat, Emilio; Wilson, Wyndham H.; Jaffe, Elaine S.; Simon, Richard H.; Yang, Liming; Powell, John; Zhao, Hong; Goldschmidt, Neta; Chiorazzi, Michael; Staudt, Louis M.

doi:10.1056/nejmoa041869

Cited by 1,280 publications

(1,034 citation statements)

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“…Indeed, gene expression of, for example, IL7 receptor and STAT4 is part of the favorable immune response 1 signature of FL. 40 In our FL collective, the expression of pSTAT5 correlated with higher amounts of tumor-infiltrating regulatory T cells, which are also known to be associated with favorable outcomes. 25 Finally, we confirmed the prognostic importance of pSTAT3 in activated B-cell-like DLBCL, which was recently observed by others, 18 as our own nongerminal center DLBCL expressing pSTAT3 had also an inferior disease-specific survival, again indicating the oncogenic potential of pSTAT3.…”

Section: Discussionmentioning

confidence: 73%

“…39 Taking into account ROC-determined cutoff values of the respective markers, another noteworthy finding of our study was the identification of the favorable prognostic value of the concomitant pJAK2 and pSTAT5 expression in FL. One of the several possible explanations for this prognostic effect of the concomitant pJAK2 and pSTAT5 expression could be sought in the known ongoing immunological cross talk in a particular group of FL with better prognosis, 40 immunological cross talk being mediated by members of the STAT family at the intracellular site. Indeed, gene expression of, for example, IL7 receptor and STAT4 is part of the favorable immune response 1 signature of FL.…”

Section: Discussionmentioning

confidence: 99%

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Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas

et al. 2009

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The Janus kinase 2 (JAK2)-signal transducers and activators of transcription (STAT) pathway plays an important role in hematological malignancies. Mutations and translocations of the JAK2 gene, mapped at 9p24, lead to constitutive activation of JAK2 and its downstream targets. The presence of JAK2 mutations in lymphomas has been addressed in larger cohorts, but there are little systemic data on numerical and structural JAK2 aberrations in lymphoid neoplasms. To study the molecular epidemiology of these aberrations and the consecutive activation of the JAK2-STAT pathway in lymphomas, we examined 527 cases, covering the most common entities, in a tissue microarray by fluorescent in situ hybridization with breakable JAK2 probes, and immunohistochemistry for phosphorylated JAK2 (pJAK2) and its preferred downstream pSTAT3 and pSTAT5. 9p24 gains were detected in 6/17 (35%) primary mediastinal B-cell lymphomas (PMBCLs), 25/77 (33%) Hodgkin's lymphomas (HLs), 3/16 (19%) angioimmunoblastic T-cell lymphomas (AILTs) and 1/5 ALK1 þ anaplastic large cell lymphomas (ALCLs); breaks were observed only in three cases. pJAK2 expression was most prevalent in PMBCL, peripheral T-cell lymphomas and HL. pSTAT3 predominated in ALCLs, HLs, AILTs, PMBCLs and peripheral T-cell lymphomas. pSTAT5 expression was detected frequently in follicular lymphomas, diffuse large B-cell lymphomas and AILTs. 9p24 gains correlated with increased proportions of tumor cells expressing pJAK2 (P ¼ 0.002) and pSTAT3 (P ¼ 0.001). In follicular lymphomas, concomitant expression of pJAK2 and pSTAT5 was linked to better prognosis, whereas expression of pSTAT3 in nongerminal center-like diffuse large B-cell lymphomas could identify a patient group with an inferior outcome. Our findings stress that despite the rarity of activating JAK2 mutations in lymphomas, JAK2 is recurrently targeted by numerical, and rarely by structural, genetic aberrations in distinct lymphoma subtypes and that JAK2-STAT pathway may play a role in lymphomagenesis. Modern Pathology (2009) 22, 476-487; doi:10.1038/modpathol.2008; published online 9 January 2009 Keywords: Janus kinase 2; pSTAT3; pSTAT5; FISH; gains 9p24; lymphoma Genetic alterations of tyrosine kinases play an important oncogenic role. 1 The V617F and the less common K539L mutations of the Janus kinase 2 (JAK2) gene have been shown to be key pathogenic players in chronic myeloproliferative diseases. [2][3][4] Recently, translocations involving the JAK2 locus such as t(9;12)(p24;p23), t(8;9)(p24;q11.2), t(3;9) (q21;p24) and t(8;9)(p22;p24) were suggested to be of oncogenic importance in various hematological neoplasms, such as acute lymphoblastic and myelogenous leukemias, atypical chronic myeloid leukemias, myelodysplastic/myeloproliferative diseases and peripheral T-cell lymphomas. [5][6][7][8][9][10][11] Gains of JAK2 gene dosage, particularly due to trisomy 9p24, which is recurrent in classical Hodgkin's lymphoma

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas

et al. 2009

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“…Rather, extrinsic factors present within the tumor microenvironment likely contribute to the growth and survival of malignant T cells, a contention supported by the observation that cytokine supplementation or the provision of T-cell costimulatory signals supports the growth of malignant T cells in vitro [37,39,40]. Both gene-expression profiling and immunohistochemistry-based studies have recently highlighted the important contribution of nonmalignant cells, including monocyte-derived lymphoma-associated macrophages, in the pathogenesis of both Hodgkin and non-Hodgkin lymphomas [41][42][43]. Similarly, malignant T cells in the skin are frequently associated with dendritic cells and immunohistochemistry-based studies have clearly demonstrated an abundant infiltrate of both lymphoma-associated macrophages and dendritic cells, many of which may be actively recruited into the tumor microenvironment by tumor-derived chemokines [44,45].…”

Section: Immunopathogenesismentioning

confidence: 99%

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

Wilcox

2011

American J Hematol

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Disease overview: Cutaneous T‐cell lymphomas are a heterogenous group of T‐cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis fungoides (MF) or Sézary syndrome (SS).Diagnosis: The diagnosis of MF or SS requires the integration of clinical and histopathologic data.Risk‐adapted therapy: Tumor, node, metastasis, and blood (TNMB) staging remains the most important prognostic factor in MF/SS and forms the basis for a “risk‐adapted,” multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin‐directed therapies is preferred, as both disease‐specific and overall survival for these patients is favorable. In contrast, patients with advanced‐stage disease with significant nodal, visceral, or blood involvement are generally approached with biologic‐response modifiers, denileukin diftitox, and histone deacetylase inhibitors before escalating therapy to include systemic, single‐agent chemotherapy. Multiagent chemotherapy may be used for those patients with extensive visceral involvement requiring rapid disease control. In highly‐selected patients with disease refractory to standard treatments, allogeneic stem‐cell transplantation may be considered. Am. J. Hematol., 2011. © 2011 Wiley‐Liss, Inc.

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“…Gene expression profiling studies of various cancers have discovered consistent gene expression patterns associated with a histological or clinical phenotype and discovering subtypes of cancers previously unidentified with conventional technologies (Alizadeh et al, 2000;van de Vijver et al, 2002;Bullinger et al, 2004;Dave et al, 2004;Lapointe et al, 2004;Valk et al, 2004;Lee et al, 2004a;Roepman et al, 2005). This approach promises to provide diagnostic and prognostic markers that can be clinically used in the near future (Lossos et al, 2004).…”

Section: Integrative Functional Genomicsmentioning

confidence: 99%

Comparative and integrative functional genomics of HCC

2006

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Global gene expression profiling of hepatocellular carcinoma (HCC) is a promising new technology that has already refined the diagnosis and prognostic predictions of HCC patients. This has been accomplished by identifying genes whose expression pattern is associated with clinicopathological features of HCC tumors. Molecular characterization of HCC from gene expression profiling studies will undoubtedly improve the prediction of treatment responses, selection of treatments for specific molecular subtypes of HCC and ultimately the clinical outcome of HCC patients. The research focus is now shifting toward the identification of genetic determinants that are components of the specific regulatory pathways altered in cancers, and that may constitute novel therapeutic targets. Here we review the recent advances in gene expression profiling of HCC and discuss the future strategies for analysing large and complicated data sets from microarray studies and how to integrate these with diverse genomic data.

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Prediction of Survival in Follicular Lymphoma Based on Molecular Features of Tumor-Infiltrating Immune Cells

Abstract: The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.

Cited by 1,280 publications

References 29 publications

Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas

Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

Comparative and integrative functional genomics of HCC

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