Abstract
Natural killer (NK) cell lymphomas/leukemias are rare neoplasms with an aggressive clinical behavior. The majority of the cases belong to extranodal NK/T-cell lymphoma, nasal type (ENKTL) in the current WHO classification scheme. Gene-expression profiling (GEP) of 21 ENKTL and NK-cell lymphoma/leukemia patients, 17 NK- and T-cell lines and 5 indolent NK-cell large-granular-lymphocytic proliferation was performed and compared with 125 peripheral T-cell lymphoma (PTCL) patients previously studied. The molecular classifier derived for ENKTL patients was comprised of 84 transcripts with the majority of them contributed by the neoplastic NK cells. The classifier also identified a set of γδ-PTCLs both in the ENKTL cases as well as in cases initially classified as PTCL-not otherwise specified. These γδ-PTCLs expressed transcripts associated with the T-cell receptor (TCR)/CD3 complex, suggesting T cell rather than NK-cell lineage. They were very similar to NK-cell tumors by GEP, but were distinct from cytotoxic (αβ)-PTCL and hepatosplenic T-cell lymphoma, indicating derivation from an ontogenically and functionally distinct subset of γδ T cells. They showed distinct expression of Vγ9, Vδ2 transcripts and were positive for TCRγ, but negative for TCRβ by immunohistochemistry. Targeted inhibition of two oncogenic pathways (AURKA and NOTCH-1) by small-molecular inhibitors induced significant growth arrest in NK-cell lines, thus providing a rationale for clinical trials of these inhibitors in NK-cell malignancies.
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References
Jaffe ES . Classification of natural killer (NK) cell and NK-like T-cell malignancies. Blood 1996; 87: 1207–1210.
Oshimi K . Leukemia and lymphoma of natural killer lineage cells. Int J Hematol 2003; 78: 18–23.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al. WHO Classification: Pathology and Genetics of Tumors of Haematopoietic and Lymphoid Tissues, 4th edn (Vol 2) IARC Press: Lyon, France, 2008.
Vose J, Armitage J, Weisenburger D . International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/t-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2008; 26: 4124–4130.
Sokol L, Loughran Jr TP . Large granular lymphocyte leukemia. Oncologist 2006; 11: 263–273.
Li YX, Yao B, Jin J, Wang WH, Liu YP, Song YW et al. Radiotherapy as primary treatment for stage IE and IIE nasal natural killer/T-cell lymphoma. J Clin Oncol 2006; 24: 181–189.
Au WY, Weisenburger DD, Intragumtornchai T, Nakamura S, Kim WS, Sng I et al. Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project. Blood 2009; 113: 3931–3937.
Chiang AK, Chan AC, Srivastava G, Ho FC . Nasal T/natural killer (NK)-cell lymphomas are derived from Epstein-Barr virus-infected cytotoxic lymphocytes of both NK- and T-cell lineage. Int J Cancer 1997; 73: 332–338.
Gaulard P, Bourquelot P, Kanavaros P, Haioun C, Le Couedic JP, Divine M et al. Expression of the alpha/beta and gamma/delta T-cell receptors in 57 cases of peripheral T-cell lymphomas. Identification of a subset of gamma/delta T-cell lymphomas. Am J Pathol 1990; 137: 617–628.
Stein H, Dienemann D, Sperling M, Zeitz M, Riecken EO . Identification of a T cell lymphoma category derived from intestinal-mucosa-associated T cells. Lancet 1988; 2: 1053–1054.
Kumar S, Krenacs L, Medeiros J, Elenitoba-Johnson KS, Greiner TC, Sorbara L et al. Subcutaneous panniculitic T-cell lymphoma is a tumor of cytotoxic T lymphocytes. Human Pathol 1998; 29: 397–403.
Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105: 3768–3785.
Nagato T, Kobayashi H, Kishibe K, Takahara M, Ogino T, Ishii H et al. Expression of interleukin-9 in nasal natural killer/T-cell lymphoma cell lines and patients. Clin Cancer Res 2005; 11: 8250–8257.
Oka T, Yoshino T, Hayashi K, Ohara N, Nakanishi T, Yamaai Y et al. Reduction of hematopoietic cell-specific tyrosine phosphatase SHP-1 gene expression in natural killer cell lymphoma and various types of lymphomas/leukemias: combination analysis with cDNA expression array and tissue microarray. Am J Pathol 2001; 159: 1495–1505.
Huang Y, de Reynies A, de Leval L, Ghazi B, Martin-Garcia N, Travert M et al. Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal-type. Blood 2010; 115: 1226–1237.
Miyazaki K, Yamaguchi M, Imai H, Kobayashi T, Tamaru S, Nishii K et al. Gene expression profiling of peripheral T-cell lymphoma including gammadelta T-cell lymphoma. Blood 2009; 113: 1071–1074.
Iqbal J, Weisenburger DD, Greiner TC, Vose JM, McKeithan T, Kucuk C et al. Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. Blood 2010; 115: 1026–1036.
Nagata H, Konno A, Kimura N, Zhang Y, Kimura M, Demachi A et al. Characterization of novel natural killer (NK)-cell and gammadelta T-cell lines established from primary lesions of nasal T/NK-cell lymphomas associated with the Epstein-Barr virus. Blood 2001; 97: 708–713.
Dybkaer K, Iqbal J, Zhou G, Geng H, Xiao L, Schmitz A et al. Genome wide transcriptional analysis of resting and IL2 activated human natural killer cells: gene expression signatures indicative of novel molecular signaling pathways. BMC Genomics 2007; 8: 230.
Simon R, Peng A . BRB-ArrayTools User Guide, version 3.6.0. Biometric Research Branch, National Cancer Institute, National Institute of Health (available at: http://linus.nci.nih.gov/BRB-ArrayTools.html).
Wright G, Tan B, Rosenwald A, Hurt EH, Wiestner A, Staudt LM . A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc Natl Acad Sci USA 2003; 100: 9991–9996.
Tusher VG, Tibshirani R, Chu G . Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 2001; 98: 5116–5121.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102: 15545–15550.
Ormerod MG . Investigating the relationship between the cell cycle and apoptosis using flow cytometry. J Immunol Methods 2002; 265: 73–80.
Martin AR, Chan WC, Perry DA, Greiner TC, Weisenburger DD . Aggressive natural killer cell lymphoma of the small intestine. Mod Pathol 1995; 8: 467–472.
Oyoshi MK, Nagata H, Kimura N, Zhang Y, Demachi A, Hara T et al. Preferential expansion of Vgamma9-JgammaP/Vdelta2-Jdelta3 gammadelta T cells in nasal T-cell lymphoma and chronic active Epstein-Barr virus infection. Am J Pathol 2003; 162: 1629–1638.
Hahm K, Cobb BS, McCarty AS, Brown KE, Klug CA, Lee R et al. Helios, a T cell-restricted Ikaros family member that quantitatively associates with Ikaros at centromeric heterochromatin. Genes Dev 1998; 12: 782–796.
Li Y, He X, Schembri-King J, Jakes S, Hayashi J . Cloning and characterization of human Lnk, an adaptor protein with pleckstrin homology and Src homology 2 domains that can inhibit T cell activation. J Immunol 2000; 164: 5199–5206.
Arnulf B, Copie-Bergman C, Delfau-Larue MH, Lavergne-Slove A, Bosq J, Wechsler J et al. Nonhepatosplenic gammadelta T-cell lymphoma: a subset of cytotoxic lymphomas with mucosal or skin localization. Blood 1998; 91: 1723–1731.
van Doorn R, Dijkman R, Vermeer MH, Out-Luiting JJ, van der Raaij-Helmer EM, Willemze R et al. Aberrant expression of the tyrosine kinase receptor EphA4 and the transcription factor twist in Sezary syndrome identified by gene expression analysis. Cancer Res 2004; 64: 5578–5586.
Iqbal J, Kucuk C, Deleeuw RJ, Srivastava G, Tam W, Geng H et al. Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies. Leukemia 2009; 23: 1139–1151.
Yang H, Ou CC, Feldman RI, Nicosia SV, Kruk PA, Cheng JQ . Aurora-A kinase regulates telomerase activity through c-Myc in human ovarian and breast epithelial cells. Cancer Res 2004; 64: 463–467.
Dutta-Simmons J, Zhang Y, Gorgun G, Gatt M, Mani M, Hideshima T et al. Aurora kinase A is a target of Wnt/beta-catenin involved in multiple myeloma disease progression. Blood 2009; 114: 2699–2708.
Liu Q, Kaneko S, Yang L, Feldman RI, Nicosia SV, Chen J et al. Aurora-A abrogation of p53 DNA binding and transactivation activity by phosphorylation of serine 215. J Biol Chem 2004; 279: 52175–52182.
Klein A, Flugel D, Kietzmann T . Transcriptional regulation of serine/threonine kinase-15 (STK15) expression by hypoxia and HIF-1. Mol Biol Cell 2008; 19: 3667–3675.
Suzuki R . Leukemia and lymphoma of natural killer cells. J Clin Exp Hematopathol 2005; 45: 51–70.
Chan JK, Sin VC, Wong KF, Ng CS, Tsang WY, Chan CH et al. Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm. Blood 1997; 89: 4501–4513.
Matano S, Nakamura S, Nakamura S, Annen Y, Hattori N, Kobayashi K et al. Monomorphic agranular natural killer cell lymphoma/leukemia with no Epstein-Barr virus association. Acta Haematol 1999; 101: 206–208.
Yagita M, Huang CL, Umehara H, Matsuo Y, Tabata R, Miyake M et al. A novel natural killer cell line (KHYG-1) from a patient with aggressive natural killer cell leukemia carrying a p53 point mutation. Leukemia 2000; 14: 922–930.
Chen IM, Whalen M, Bankhurst A, Sever CE, Doshi R, Hardekopf D et al. A new human natural killer leukemia cell line, IMC-1. A complex chromosomal rearrangement defined by spectral karyotyping: functional and cytogenetic characterization. Leuk Res 2004; 28: 275–284.
Zhang Y, Nagata H, Ikeuchi T, Mukai H, Oyoshi MK, Demachi A et al. Common cytological and cytogenetic features of Epstein-Barr virus (EBV)-positive natural killer (NK) cells and cell lines derived from patients with nasal T/NK-cell lymphomas, chronic active EBV infection and hydroa vacciniforme-like eruptions. Br J Haematol 2003; 121: 805–814.
Lopez RD, Xu S, Guo B, Negrin RS, Waller EK . CD2-mediated IL-12-dependent signals render human gamma delta-T cells resistant to mitogen-induced apoptosis, permitting the large-scale ex vivo expansion of functionally distinct lymphocytes: implications for the development of adoptive immunotherapy strategies. Blood 2000; 96: 3827–3837.
Deusch K, Luling F, Reich K, Classen M, Wagner H, Pfeffer K . A major fraction of human intraepithelial lymphocytes simultaneously expresses the gamma/delta T cell receptor, the CD8 accessory molecule and preferentially uses the V delta 1 gene segment. Eur J Immunol 1991; 21: 1053–1059.
Carding SR, Egan PJ . Gammadelta T cells: functional plasticity and heterogeneity. Nat Rev Immunol 2002; 2: 336–345.
Mastovich S, Ratech H, Ware RE, Moore JO, Borowitz MJ . Hepatosplenic T-cell lymphoma: an unusual case of a gamma delta T-cell lymphoma with a blast-like terminal transformation. Human Pathol 1994; 25: 102–108.
Przybylski GK, Wu H, Macon WR, Finan J, Leonard DG, Felgar RE et al. Hepatosplenic and subcutaneous panniculitis-like gamma/delta T cell lymphomas are derived from different Vdelta subsets of gamma/delta T lymphocytes. J Mol Diagn 2000; 2: 11–19.
Boulland ML, Kanavaros P, Wechsler J, Casiraghi O, Gaulard P . Cytotoxic protein expression in natural killer cell lymphomas and in alpha beta and gamma delta peripheral T-cell lymphomas. J Pathol 1997; 183: 432–439.
Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J et al. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 2002; 416: 648–653.
Saridakis V, Sheng Y, Sarkari F, Holowaty MN, Shire K, Nguyen T et al. Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization. Mol Cell 2005; 18: 25–36.
Katayama H, Sasai K, Kawai H, Yuan ZM, Bondaruk J, Suzuki F et al. Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet 2004; 36: 55–62.
Bayliss R, Sardon T, Vernos I, Conti E . Structural basis of Aurora-A activation by TPX2 at the mitotic spindle. Mol Cell 2003; 12: 851–862.
Kufer TA, Sillje HH, Korner R, Gruss OJ, Meraldi P, Nigg EA . Human TPX2 is required for targeting Aurora-A kinase to the spindle. J Cell Biol 2002; 158: 617–623.
Lens SM, Vader G, Medema RH . The case for Survivin as mitotic regulator. Curr Opin Cell Biol 2006; 18: 616–622.
Acknowledgements
We thank Martin Bast for clinical data collection, and Kavita Patel and Lisa Bough for their technical assistance. This work was supported in part by NCI Grant 5U01/CA114778, Lymphoma SPORE P50CA136411-01(NC1) and funds from the International Peripheral T-cell Lymphoma Project and Eppley Cancer Institute Core Grant CA36727. The UNMC Microarray Core Facility is supported partially by NIH Grant P20 RR016469 from the INBRE Program of the National Center for Research Resources.
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Presented in part at the oral-session at the 51st American Society of Hematology (ASH) Annual Meeting, New Orleans, LA, 5–8 December 2009.
Supplementary Information accompanies the paper on the Leukemia website
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Iqbal, J., Weisenburger, D., Chowdhury, A. et al. Natural killer cell lymphoma shares strikingly similar molecular features with a group of non-hepatosplenic γδ T-cell lymphoma and is highly sensitive to a novel aurora kinase A inhibitor in vitro. Leukemia 25, 348–358 (2011). https://doi.org/10.1038/leu.2010.255
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DOI: https://doi.org/10.1038/leu.2010.255
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