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Natural Killer Cell Lymphoma Shares Strikingly Similar Molecular Features

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Natural Killer Cell Lymphoma Shares Strikingly Similar Molecular Features Leukemia (2011) 25, 348–358 & 2011 Macmillan Publishers Limited All rights reserved 0887-6924/11 www.nature.com/leu ORIGINAL ARTICLE Natural killer cell lymphoma shares strikingly similar molecular features with a group of non-hepatosplenic cd T-cell lymphoma and is highly sensitive to a novel aurora kinase A inhibitor in vitro J Iqbal1, DD Weisenburger1, A Chowdhury2, MY Tsai2, G Srivastava3, TC Greiner1, C Kucuk1, K Deffenbacher1, J Vose4, L Smith5, WY Au3, S Nakamura6, M Seto6, J Delabie7, F Berger8, F Loong3, Y-H Ko9, I Sng10, X Liu11, TP Loughran11, J Armitage4 and WC Chan1, for the International Peripheral T-cell Lymphoma Project 1Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA; 2Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA; 3Departments of Pathology and Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China; 4Division of Hematology and Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; 5College of Public Health, University of Nebraska Medical Center, Omaha, NE, USA; 6Departments of Pathology and Cancer Genetics, Aichi Cancer Center Research Institute, Nagoya University, Nagoya, Japan; 7Department of Pathology, University of Oslo, Norwegian Radium Hospital, Oslo, Norway; 8Department of Pathology, Centre Hospitalier Lyon-Sud, Lyon, France; 9Department of Pathology, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea; 10Department of Pathology, Singapore General Hospital, Singapore and 11Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, USA Natural killer (NK) cell lymphomas/leukemias are rare neo- Introduction plasms with an aggressive clinical behavior. The majority of the cases belong to extranodal NK/T-cell lymphoma, nasal type Natural killer (NK)-cell malignancies are rare and present (ENKTL) in the current WHO classification scheme. Gene- mainly as a lymphoma and less commonly as leukemia termed expression profiling (GEP) of 21 ENKTL and NK-cell lymphoma/ 1 leukemia patients, 17 NK- and T-cell lines and 5 indolent NK-cell aggressive NK-cell leukemia (ANKL). Extranodal NK-cell large-granular-lymphocytic proliferation was performed and lymphoma typically occurs in the nasal/paranasal areas with compared with 125 peripheral T-cell lymphoma (PTCL) patients prominent angioinvasion and angiodestruction and accompany- previously studied. The molecular classifier derived for ENKTL ing necrosis. Other extranodal sites may also be involved and patients was comprised of 84 transcripts with the majority of are frequently associated with hemophagocytic syndrome at the them contributed by the neoplastic NK cells. The classifier also 2 identified a set of cd-PTCLs both in the ENKTL cases as well advanced stage. There have also been reports of rare T-cell as in cases initially classified as PTCL-not otherwise specified. lymphomas in these locations with very similar clinicopatho- These cd-PTCLs expressed transcripts associated with the logic features, and these lesions are grouped under the heading T-cell receptor (TCR)/CD3 complex, suggesting T cell rather of extranodal NK/T-cell lymphoma, nasal type (ENKTL).3 ENKTL than NK-cell lineage. They were very similar to NK-cell tumors shows strong geographic predilection, with much higher by GEP, but were distinct from cytotoxic (ab)-PTCL and frequencies in East Asia and Central and South America.4 ANKL hepatosplenic T-cell lymphoma, indicating derivation from an ontogenically and functionally distinct subset of cd T cells. is a related disorder with highly aggressive clinical course They showed distinct expression of Vc9, Vd2 transcripts and in contrast to the chronic lymphoproliferative disorder of were positive for TCRc, but negative for TCRb by immuno- NK cells.5 Although ENKTL localized to the nasal region is histochemistry. Targeted inhibition of two oncogenic pathways responsive to radiation therapy, patients with disseminated (AURKA and NOTCH-1) by small-molecular inhibitors induced disease have a very poor outcome.6,7 significant growth arrest in NK-cell lines, thus providing a There is a spectrum of lymphomas with cytotoxic (CT) rationale for clinical trials of these inhibitors in NK-cell molecules belonging to ab or gd T-cell lineage8 including malignancies. 9 Leukemia (2011) 25, 348–358; doi:10.1038/leu.2010.255; hepatosplenic gd T-cell lymphomas (HSTCL), enteropathy- published online 5 November 2010 associated T-cell lymphoma (EATCL)10 and CT T-cell lymphoma Keywords: NK-cell lymphoma; gd T-cell lymphoma; molecular of the skin and subcutaneous tissue.11,12 These tumors express classifier; gene-expression signature; NOTCH pathway; aurora the surface T-cell receptor (TCR)/CD3 complex, exhibit clonal kinase A TCR rearrangement and are negative for Epstein–Barr virus (EBV) genome in the tumor cells. It is unclear if these entities have distinct gene expression profiles (GEPs) that can distinguish them from each other and from ENKTL. Owing to the rarity of the disease and the difficulty in obtaining adequate biopsy specimens, the molecular mecha- Correspondence: Professor WC Chan, Department of Pathology and nisms underlining ENKTL are largely unknown. Only a few 13,14 Microbiology, Center for Research in Lymphoma and Leukemia, genome-wide profiling studies using NK-cell lines and a 983135 Nebraska Medical Center, Omaha, NE 68198-3135, USA. limited number of NK-cell15 and gd T-cell lymphoma cases have E-mail: [email protected] been performed.16 In this study, we have defined molecular Presented in part at the oral-session at the 51st American Society of signatures for ENKTL and related malignancies. We have also Hematology (ASH) Annual Meeting, New Orleans, LA, 5–8 December 2009. identified a number of oncogenic pathways in NK-cell tumors Received 26 February 2010; revised 17 August 2010; accepted 7 and validated the potential significance of the Notch-1 and September 2010; published online 5 November 2010 aurora kinase A pathways by inhibitor studies in vitro. Molecular features of NK-cell and cd T-cell lymphoma J Iqbal et al 349 Materials and methods determined using CellTiter-GloLuminescent-Cell Viability Assay (Promega Inc, Madison, WI, USA). Notch-1 inhibitors Patient source and cell lines (Compound-E and Compound-34, ENZO Life-Sciences, Inc, A series of ENKTL (n ¼ 18), ANKL cases (n ¼ 2) and an EBV (À) Plymouth Meeting, PA, USA) were similarly tested in NK-cell aggressive NK-cell lymphoma (n ¼ 1) diagnosed pathologically lines. B-cell line (DHL16) was used as negative and HL (L428) were studied4,7 for their GEP. We compared their GEP with a and T-cell line (Jurkat) as positive controls for Notch-1 experi- series of peripheral T-cell lymphoma (PTCL) cases from our ments. AURKA phosphorylation status and co-activators and recent study17 including 44 PTCL-not otherwise specified (NOS) substrates (TPX2, TP53 and Survivin) were evaluated by western cases, 4 HSTCL, 2 EATCL cases, 11 CT (ab)-PTCL17 and five blots (ECL Plus kit; GE-Healthcare Bio-Science, Piscataway, NJ, indolent NK-cell large-granular-lymphocytic proliferation cases. USA). Apoptosis and cell cycle analysis was performed with flow The pathology review, diagnostic criteria and clinical data for cytometry24 (BD FACScalibur, BD-Bioscience, San Jose, CA, these cases have been described.4,7 The Institutional Review USA). Analysis of the list mode data was performed using ModFit Board of the University of Nebraska Medical Center approved software (VeritySoftwarehouse, Topsham, ME, USA). this study. The characteristics of malignant NK-cell lines, gd T-cell Results lines18 and other T-cell lines are summarized in Supplementary Table 1a. The cell lines were cultured as previously described.17 19 Patient and cell line characteristics Normal resting and activated NK cells, and T-cell subsets were We have identified four distinct groups of CT lymphomas: used for comparative analysis. NK-cell lineage (NKCL), HSTCL, CT (ab)-PTCL and gd-PTCL (non-hepatosplenic, NHS) according to their lineage and gene- RNA isolation and GEP expression profile as detailed in subsequent sections, and their characteristics are summarized in Table 1a. NKCL refers to We used HG-U133 plus 2 arrays (Affymetrix Inc., Santa Clara, NK-cell lineage malignancies of ENKTL and ANKL entities. The CA, USA) for GEP as described previously.17 The raw data was uploaded in BRB-ArrayTools (version 3.7.0)20 for analysis. The classifier for ENKTL was constructed using the Bayesian Table 1a Clinical characteristics of the different groups of cytotoxic lymphomasa algorithm as described earlier.21 We selected genes at a significance level (Po0.001) and a mean fold difference (X4-fold ) between the ENKTL and PTCL groups for the Bayesian NKCL gd-PTCL HSTCL CT (NHS) (ab)-PTCL algorithm. Classification precisions were evaluated using 20 leave-one-out cross-validation. Differential gene-expression Number of cases 17 5 4 11 and pathway analysis was performed using random-variance T-test (Po0.005), significance analysis of microarrays (with Age (years) false discover rate o0.1 and X3-fold change)22 and gene- Median 49 55.5 33 58 Range (24–79) (18–87) (20–46) (41–80) set-enrichment-analysis computational programs.23 The micro- array data is available in the Gene Expression Omnibus Percentage (%) database of NCBI through the accession numbers GSE19067 Gender and GSE8059. Male 53 60 75 90 Female 47 40 25 10 Evaluation of re-classified cases IPI The re-classified cases by GEP were re-reviewed by Low (0–2) 63 100 50 50 High (3–5) 37 0 50 50 DD Weisenburger. Additional immunostains and TCRg gene rearrangement analyses were performed when feasible to Chemo evaluate the diagnoses of these cases. The antibody for TCRg CHOP like 19 80 25 75 (clone g3.20) (Thermo Scientific/Pierce Biotechnology/Endogen, Other 56 20 75 25 Rockford, IL, USA) was incubated with the slide for 2 h at 1:80 None 25 0 0 0 dilution.
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