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Aggressive Mature Natural Killer Cell Neoplasms isord D ers od & lo T r B f a n o s l f a u n s r Journal of i o u n o Lima, J Blood Disorders Transf 2013, 5:1 J ISSN: 2155-9864 Blood Disorders & Transfusion DOI: 10.4172/2155-9864.1000182 Review Article OpenOpen Access Access Aggressive Mature Natural Killer Cell Neoplasms: from Disease Biology to Disease Manifestations Margarida Lima* Department of Hematology, Laboratory of Cytometry, Hospital de Santo António, Centro Hospitalar do Porto, Multidisciplinary Unit for Biomedical Investigation, Portugal Abstract Nature killer (NK)/T cell lymphoma, nasal type, and aggressive NK-cell leukemia are rare tumors with higher prevalence in Asia, Central and South America, which are etiologically related to the Epstein Barr virus (EBV). Proteins encoded by EBV genes and non-coding viral RNAs expressed on the infected cells are involved in immune deregulation and cell transformation and lymphomagenesis occur as a consequence of multiple oncogenic events. Complex chromosomal abnormalities are frequent and loss of chromosomes 6q, 11q, 13q, and 17p are recurrent aberrations. In accordance, many genes are differentially expressed, often due to gene deletion, mutation or methylation. These include, among others, tumor suppressor genes and oncogenes, as wells as genes involved in cell signal transducer pathways, cell survival and apoptosis, cell cycle, cell motility and cell adhesion, as well as in cell communication through cytokine networks. Consequently many biochemical pathways are affected in NK-cell neoplasms, which could contribute to cancer development and progression, as well as to disease manifestations. This review focuses on the molecular and biochemical mechanisms by which EBV induces NK-cell lymphomagenesis, disrupting genes and molecules involved in crucial biological processes. Improving the knowledge in this subject will help to better understand the disease biology and clinical manifestations and to develop new treatment approaches for the NK-cell malignancies. Keywords: NK-cell neoplasms; NK/T-cell lymphoma; Nasal-type; Forkhead Transcription Factors of the O class type 3; HACE1: HECT Aggressive NK-cell leukemia; Extranodal lymphomas; Epstein Barr Domain and Ankyrin Repeat Containing E3 Ubiquitin Protein Ligase virus; Oncogenesis; Lymphomagenesis; Angioinvasion; Vascular 1; HS: Hemophagocytic Syndrome; ICAM-1: Intercellular Adhesion destruction; Hemophagocytic syndrome Molecule -1 (CD54); IFN: Interferon; IGF: Insulin-like Growth Factor; IGIF: Interferon-Gamma Inducing Factor (IL-18); IL: Interleukin; Abbreviations: AIM1: Absent in Melanoma-1; ANKCL: Aggressive IL18BP: IL-18 Binding Protein; IL-6R: Interleukin 6 Receptor; IP- NK-cell Leukemia; ATG5: Autophagy related 5; ATM: Ataxia 10: IFN-Gamma-Inducible Protein 10 (CXCL10); Jak: Janus kinase; Telangiectasia Mutated; ATR: ATM Rad3-related; AURKA: Aurora K-RAS: v-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog; kinase A; BBC3: BCL2-Binding Component 3; BIM: Bcl-2-like Protein LACE1: Lactation Elevated 1; LFA: Leukocyte Function Adhesion 11; BIRK5: Baculoviral Inhibitor of apoptosis Repeat-containing 5; Molecule; LFA-1: Lymphocyte Function Molecule Type 3 (CD11a); BLIMP1: B-lymphocyte-Induced Maturation Protein 1; BM: Bone Marrow; BTAK: STK15 or Aurora kinase A (AURKA); CAM: Cell LFA-3: Lymphocyte Function Molecule Type 3 (CD58); LMP: EBV- Adhesion Molecules; CCL2: C-C Motif Chemokine Ligand Type 2 Encoded Latent Membrane Protein; MCP-1: Monocyte Chemotactic (MCP-1); CCL3: C-C Motif Chemokine Ligand Type 3 (MIP-1alpha); Protein-1 (CCL2); MCP-2: Monocyte Chemotactic Protein-1 (CCL8); CCL4: C-C Motif Chemokine Ligand type 4 (MIP-1beta); CCL5: MIB1: Mindbomb E3 Ubiquitin Protein Ligase 1 also known as Ki67; C-C motif chemokine ligand type 5 (RANTES); CCL8: C-C motif MIG: Monokine Induced by Gamma Interferon (CXCL9); MIG: chemokine Ligand type 8 (MCP-2); CCL18: C-C Motif Chemokine Monokine Induced by IFN-Gamma (CXCL9); MIP: Macrophage Ligand Type 18 (PARC); CCL19: C-C Motif Chemokine Ligand Type Inflammatory Protein; MIP-1alpha: Macrophage inflammatory 19 (ELC); CCNA2: Cyclin-A2; CCR5: C-C Motif Chemokine Receptor protein-1alpha (CCL3); MIP-1beta: Macrophage Inflammatory Type 5 (CD195); CD11b: Integrin alpha M Complement Receptor Type Protein-1beta (CCL4); MMP: Matrix Metalloproteinases; MYC: v-myc 3; CD49b: Integrin alpha 2 alpha 2 Subunit of VLA-2 Receptor; CD49d: Myelocytomatosis Viral Oncogene Homolog; NFκB: Nuclear Factor Integrin alpha 4 alpha 4 Subunit of VLA-4 Receptor; CDK: Cyclin- κB; NK: Natural Killer; NKTCL: NK/T Cell Lymphoma; NOTCH: Dependent Kinases; CGH: Comparative Genomic Hybridization; Notch Homolog translocation-associated; PAR: Plasminogen Activator CHK: Checkpoint Protein Kinases; C-KIT: Cellular homolog of Receptor; PARC: Pulmonary and Activation-Regulated PARC (CCL18); the feline sarcoma viral oncogene v-KIT; CLPD-NK: Chronic Lymphoproliferative Disorders of NK-cells; CPP32: Apoptosis-Induced Cysteine Protease 32; CTL: Cytotoxic T lymphocytes; CXCL1: C-X-C *Corresponding author: Margarida Lima, Department of Hematology, Motif Chemokine Ligand Type 1 (IL-18); CXCL9: C-X-C Motif Laboratory of Cytometry, Hospital de Santo António, Centro Hospitalar do Porto, Chemokine Ligand Type 9 (MIG); CXCL10: C-X-C Motif Chemokine Rua D Manuel II, s/n 4099-001 Porto, Portugal, Tel: 351-22-2077500; Fax: 351-22- 600480; E-mail: [email protected], [email protected] Ligand Type 10 (IP-10); CXCL11: C-X-C Motif Chemokine Ligand Type 11 (IP9); CXCL12: C-X-C Motif Chemokine Ligand Type 12 (SDF-1); Received November 25, 2013; Accepted December 13, 2013; Published December 15, 2013 CXCR1: C-X-C Motif Chemokine Ligand Receptor Type 1 (CD181); CXCR3: C-X-C Motif Chemokine Ligand Receptor Type 3 (CD183); Citation: Lima M (2013) Aggressive Mature Natural Killer Cell Neoplasms: from CYR61: Cysteine-rich Angiogenic Inducer 61; DEFB: Defensin Beta; Disease Biology to Disease Manifestations. J Blood Disorders Transf 5: 182. doi: 10.4172/2155-9864.1000182 EBV: Epstein-Barr Virus; ELC: EBI1 Ligand Chemokine (CCL18); FasL: Fas Ligand (CD95L); FGF: Fibroblast Growth Factor; FLIP: Copyright: © 2013 Lima M. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted FLICE-like Inhibitory Protein; FOX: Forkhead Family of Transcription use, distribution, and reproduction in any medium, provided the original author and Factors; FOXO: Forkhead Transcription Factors of the O class; FOXO3: source are credited. J Blood Disorders Transf ISSN: 2155-9864 JBDT, an open access journal Volume 5 • Issue 1 • 1000182 Citation: Lima M (2013) Aggressive Mature Natural Killer Cell Neoplasms: from Disease Biology to Disease Manifestations. J Blood Disorders Transf 5: 182. doi: 10.4172/2155-9864.1000182 Page 2 of 10 PDGF: Platelet-Derived Growth Factor; PDGFR: Platelet-Derived features of the NKTCL and ANKCL [18]. Herein, we review the Growth Factor Receptor; PDGFRA: Platelet-Derived Growth Factor molecular and biochemical mechanism involved in oncogenesis and Receptor Alpha; PI3K: Phosphatidylinositol 3 Kinase; PI9: Protease disease manifestations of these aggressive NK-cell neoplasms. Inhibitor Type 9; PKB: Protein Kinase B; POPDC3: Popeye Domain Containing 3; PRDM1: PR Domain Zinc Finger Protein 1; PREP: Prolyl Mechanisms involved in NK-cell oncogenesis Endopeptidase; PTEN: Phosphatase and Tensin Homolog; PUMA: p53 Although the pathogenesis of the NK-cell tumors remains Upregulated Modulator of Apoptosis; RNA: Ribonucleic acid; SDF-1: poorly understood, some insights have been gained in the recent Stromal Cell-Derived Factor-1 (CXCL12); STAT: Signal Transducers years concerning the mechanisms involved in oncogenesis and and Activators of Transcription; STK15: also known as BTAK or Aurora disease progression [43-45]. In accordance, disruptions of molecular Kinase A (AURKA); TGF: Transforming Growth Factor; Th: T Helper; mechanisms and cell signaling pathways involved in NK-cell Th1: T Helper Type 1; Th2: T Helper Type 2; TIA-1: T-cell-Restricted maturation may lead to the development of NK cell malignancies [43]. Intracellular Antigen; TNF: Tumor Necrosis Factor; TNFAIP3: Tumor Multiple genes involved in crucial biological processes are differentially Necrosis Factor Alpha-Induced Protein 3 also known as A20; TNFR: expressed in NK-cell neoplasms, often due to deletions, mutations Tumor Necrosis Factor Receptor; TP53: Tumor Protein p53; TP73: or abnormal methylation patterns (Table 1). However, in NK-cell Tumor Protein p73; TRAF: TNF Receptor Associated Factor; uPAR: tumors, where necrosis usually associates with tissue infiltration by Urokinase-Type Plasminogen Activator Receptor; VCAM-1: Vascular mesenchymal cells and reactive inflammatory cells, it is often difficult Cell Adhesion Molecule Type 1 (CD106); VEGF: Vascular Endothelial to directly attribute the molecular alterations to the tumor cells without Growth Factor; vIL-10: viral homologue of Interleukin 10; WHO: confirming it with biochemical or immunohistochemical studies. World Health Organization. Chromosomal and genomic abnormalities Introduction Despite the difficulties in obtaining representative NKTCL Natural killer (NK) cell neoplasms are rare diseases that are much biopsy samples, several cytogenetic, genetic and genomic studies, more prevalent in Central and South America and Eastern countries for using Comparative Genomic Hybridization (CGH) and loss of reasons that are not completely clear. They comprise a limited spectrum heterozygosity techniques,
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