Disease location ENKTCL-NT is a disease of malignant NK or, very much less often, cytotoxic T cells. Unlike most other lymphomas, which typically develop in and involve lymphatic tissues (particularly lymph nodes and spleen), ENKTCL-NT commonly develops in non-lymphatic tissues. This difference in distribution probably reflects the occupancy of the T cell and B cell precursors to most lymphomas in lymphatic tissues versus the frequent occupancy of the NK and cytotoxic T cells precursors to ENTCL-NT in non-lymphatic tissues. Genes ENKTCL-NT is thought to arise from the expression of EBV genes in the infected NK or cytotoxic T cells and the ability of these genes to cause the cells they infect to overexpress and acquire mutations in key genes that regulate cell growth, immortalization, invasiveness, and ability to evade normal control mechanisms, particularly immune surveillance. Since these gene-related abnormalities are multiple and vary between patients, it is not clear which contribute to the development and/or progression of ENKTCL-NT. Clinical studies are therefore examining targeted therapy tactics to determine which gene abnormalities contribute to, and which drugs targeting these abnormalities are useful in treating, ENKTCL-NT. EBV genes Infected cells carry ~10 cytosolic EBV episomes, i.e. gene-bearing viral DNA particles. In the premalignant precursor NK and cytotoxic T cells of ENKTCL-NT, these episomes express only some of their many latency genes, i.e. genes which promote the virus's latency rather than lytic phase of infectivity. EBV has three different latency phases, I, II, and III, in each of which different sets of latency genes are expressed to establish different controls on the cells which they infect. In the premalignant cells of ENKTCL-NT, EBV express latency II genes such as EBNA-1, LMP-1, LMP-2A, and LMP-2B protein-producing genes; EBER-1 and EBER-2 non-coding RNA-producing genes (see EBV non-coding RNAs); and certain BART microRNA-producing genes (see EBV microRNAs). LMP1 protein induces infected cells to overexpress genes that produce cMyc, NF-κB, and BCL2 proteins which when overexpressed block these cells' apoptosis (i.e. cell death) response to injury or the host's immune system and promote their survival and proliferation; LMP2A and LMP2B proteins induce infected cells to overexpress the genes that make AKT and B cell receptor proteins and to activate the NF-κ pathway which when over-activated blocks these cells' apoptosis response and promotes their survival and proliferation; EBER 1 and 2 non-coding RNAs induce infected cells to overexpress the gene that makes the interleukin 10 protein which when overexpressed may promote its parent cells to proliferate and avoid the host's immune system; and certain BART microRNAs may help infected cells avoid attack by the hosts immune system and modify their notch signaling pathway thereby promoting their proliferation. In consequence, the EBV latency II genes force infected cells to become immortal, proliferate excessively, invade tissues, and avoid attack by the hosts' immune system. Due at lease in part to these imposed factors, the infected cells may acquire other genetic abnormalities that further promote their malignant behavior. Infected cell genes The rapidly proliferating and immortalized EBV-infected NK/T cells accumulate numerous changes in the expression or activity of their genes by acquisition of chromosome deletions, gene mutations, and changes in gene expression. Chromosomes Deletions in the long (i.e. "q") arm at position 21-25 (notated as 6q21-25) from one of the two chromosome 6's was an early finding in occasional cases of ENKTCL-NT. This deletion removes one of the two copies of several tumor suppressor genes (i.e. genes that protect cells from becoming malignant) such as HACE1, PRDM1, FOXO3, and PTPRK. Subsequent studies showed that the disease is also occasionally associated with losses in the short arm of chromosome 8 at position 11.23 (8p11.23) which for unclear reasons are associated with a poor prognosis, and occasional losses at position 11l.2 in the q arm of chromosome 14 (14q11.2) which correlates with the ENKTCL-NT malignancy being of cytotoxic T cell origin. EBV-infected NK and T cells may also occasionally develop chromosome segregation errors during mitosis and consequently divide into daughter cells which possess too few or too many chromosomes and thereby exhibit chaotic losses or increases in the expression of the genes located on these chromosomes. Mutated genes Second generation sequencing methods have uncovered numerous genes which are mutated in the malignant cells of ENKTCL-NT. These mutated genes and their product proteins have the following a) mutation rates in ENKTCL-NT; b) normal functions; c) gains or losses of activity; d) pro-malignant effects on EN/T cells and e) clinical impacts on the course of ENKTCL-NT: Gene Product Mutation rate Function Mutation type Influence on cell function Clinical impact on ENKTCL-NT TP53 p53 13-62% tumor suppressor gain promotes cell proliferation, survival, migration, invasiveness, and metastasis correlates with advanced stage and poor prognosis DDX3X DDX3X 12-20% tumor suppressor loss lost ability to inhibit proliferation correlates with advanced stage and poor prognosis STAT3 STAT3 8-26% JAK-STAT signaling pathway component gain promotes cell proliferation and survival unknown STAT5B STAT5B ~2-6% JAK-STAT signaling pathway component gain promotes cell proliferation and survival unknown JAK3 JAK3 0-35% JAK-STAT signaling pathway component gain promotes cell proliferation and survival unknown MGA MAX dimerization protein ~8% tumor suppressor loss unknown unknown MLL2 MLL2 7-80% histone methyltransferase, tumor suppressor loss reduces cellular differentiation, possibly promoting cell proliferation and survival unknown BCOR BCL-6 corepressor 21-32% inhibits BCL-5, may regulate apoptosis loss may increase cell survival unknown ECSIT ECSIT 19% element in TGF-β/BMP/signaling pathways gain activates NF-κB to promote cell survival and prolifaration correlates with advanced stage and poor prognosis ARID1A ARID1A 4-8% a SWI/SNF protein that regulates expression of other proteins loss unknown unknown MCL1 MCL1 most cases a SWI/SNF protein that regulates expression of other proteins loss unknown unknown In the above table, ARID1A protein stands for AT-rich interactive domain-containing protein 1A and ECSIT protein stands for evolutionarily conserved signaling intermediate in Toll pathway; mitochondrial. A gain of function mutation in the ECSIT gene that changes the amino acid at the 140 position in its product protein from valine to alanine (i.e. V140A) is associated with a high incidence of ENKTCL-NT being complicated by the development of life-threatening Hemophagocytic lymphohistiocytosis and thereby a relatively high mortality rate. Numerous other genes are rarely (i.e. ≤2% of cases) mutated in ENKTCL-NT. These include JAK1, MLL3, ARID1A, EP300, ASXL3, MSN, FAT4, NARS, IL6R, MGAM, CHPF2, (see) and MIR17HG ((see). Overexpressed genes ENKTCL-NT malignant cells overexpress NF-κB, a cellular signaling transcription factor that when up-regulated promotes these cells' proliferation and survival. They also overexpress: 1) aurora kinase A, a serine/threonine-specific protein kinase that when up-regulated in the cancer setting promotes these cells' invasiveness and to develop chromosome segregation errors during mitosis that result in daughter cells having too few or too many chromosome; 2) members of the inhibitor of apoptosis family of proteins including survivin, Bcl-xL, and MCL1 which when up-regulated suppress programmed cell death to promote these cell's survival and resistance to attack by the host immune system; 3) multidrug resistance protein 1, a surface membrane protein that when up-regulated causes these cells to greatly increases the export of anthracyclines such as Adriamycin and Daunomycin thereby rendering them resistant to this class of chemotherapy drugs; 4) EZH2, a histone methyltransferase that when up-regulated indirectly promotes these cells' growth; 5) runt-related transcription factor 3 that when up-regulated indirectly promotes the survival and proliferation of these cells; and 6) programmed death-ligand 1 (PD-L1), that when up-regulated increases the ability of these cells to avoid attack by the host's immune system. Signaling pathways In consequence of, or addition to the cited genetic abnormalities, ENKTCL-NT malignant cells have overly active the; JAK-STAT signaling pathway that in the cancer setting promotes cell proliferation, survival, and other pro-malignant behaviors; platelet-derived growth factor signaling pathway that in the cancer setting promotes cell survival and proliferation; Notch signaling pathway that in the cancer setting promotes cellular differentiation and proliferation; and NF-κB signaling that in the cancer setting promotes cell survival and proliferation. Studies suggest that that overactive VEGF receptor and Protein kinase B signaling pathways may also play a role in the pathogenesis of ENKTCL-NT.) Epigenetic abnormalities Studies on cultured malignant NK cells and/or patient tissue specimens find that numerous genes are hypermethylated at their promoter sites and therefore are silenced, i.e. make less or none of their protein products. This silencing has been detected in numerous proteins expressed by cultured NK cells (e.g. BCL2L11, DAPK1, PTPN6, TET2, SOCS6, PRDM1, AIM1, HACE, p15, p16, p73, MLH1, RARB, and ASNS) and the MIR146A gene for its miR-146a microRNA product. Studies conducted on the expression of microRNAs in cultured malignant NK cells have also revealed that many are either over- or under-expressed compared to non-malignant cultured NK cells. This dysregulation of these microRNA genes may reflect the action of products expressed by certain EBV genes and/or the overexpression of the infected cells' MYC gene. In all cases, the epigenetic dysregulation of these genes requires further study to determine its significance for the development and progression of ENKTCL-NT.
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