Genetics and genomics of extranodal natural killer/T cell lymphoma: from etiology to treatment

Abstract

Extranodal natural killer/T cell lymphoma (NKTCL) is a heterogenous and unique epidemiological non-Hodgkin’s lymphoma, which is strongly associated with Epstein-Barr virus (EBV) infection. Based on the development of various sequencing methods and molecular biology technologies, genome- and transcriptome-wide association studies of NKTCL have provided insight into the etiology and pathogenesis of NKTCL. Comparative genomic hybridization detected variations in tumor suppressor genes such as PRDM1, RUNX3, and EZH2. Whole-exome sequencing identified pathogenic variant such as DDX3X, and TP53. Signal pathways such as the Janus kinase/signal transduction and activator of transcription pathway and nuclear factor kappaB pathway are frequently abnormal in NKTCL. In addition, programmed death-1, programmed death ligand-1, and the human leukocyte antigen risk alleles are significantly associated with NKTCL pathogenesis. Meanwhile, epigenetics analysis has also exposited changes such as PTPRK, HACE1, microRNAs, and long non-coding RNAs, which play important role on the development and biology of NKTCL. EBV infection is tightly correlated with NKTCL. Viral genomic alterations and lytic genes of EBV are reported to have pathogenic effects on host cells that contribute to the etiology of NKTCL. We summarize the genomic and genetic alterations during the pathogenesis and development of NKTCL and exhibit the potential therapeutic targets that are worth exploring in future research and clinical trials.

Keywords

Extranodal natural killer/T cell lymphoma / Epstein-Barr virus / genomics / genetics / therapeutic targets

References

[1] HarabuchiY,KatauraA,KinoshitaT.Epstein-Barr virus in nasal T-cell lymphomas in patients with lethal midline granuloma.Lancet1990;335:128-30

[2] AozasaK,TajimaK.Nation-wide study of lethal mid-line granuloma in Japan: frequencies of wegener's granulomatosis, polymorphic reticulosis, malignant lymphoma and other related conditions.Int J Cancer1989;44:63-6

[3] GaalK,HernandezAM.Sinonasal NK/T-cell lymphomas in the United States.Am J Surg Pathol2000;24:1511-7

[4] NagataH,KimuraN.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.Blood2001;97:708-13

[5] KoYH,KimWS,MoonWS.Clinicopathologic and genotypic study of extranodal nasal-type natural killer/T-cell lymphoma and natural killer precursor lymphoma among Koreans.Cancer2000;89:2106-16

[6] GualcoG,ChioatoL,NatkunamY.Clinicopathologic and molecular features of 122 Brazilian cases of nodal and extranodal NK/T-cell lymphoma, nasal type, with EBV subtyping analysis.Am J Surg Pathol2011;35:1195-203

[7] KaurK,BhardwajN.Spectrum of cytomorphological features of extranodal NK/T-cell lymphoma, nasal type.Cytopathology2019;30:393-401

[8] HuangY,WeiR.CD20-positive extranodal NK/T cell lymphoma: clinicopathologic and prognostic features.Virchows Arch2020;477:873-83

[9] AuWY,IntragumtornchaiT.International Peripheral T-Cell Lymphoma ProjectClinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project.Blood2009;113:3931-7

[10] NagatoT,OharaK.Programmed death-ligand 1 and its soluble form are highly expressed in nasal natural killer/T-cell lymphoma: a potential rationale for immunotherapy.Cancer Immunol Immunother2017;66:877-90

[11] KwongYL.Natural killer-cell malignancies: diagnosis and treatment.Leukemia2005;19:2186-94

[12] FoxCP,KoY.Survival outcomes of patients with extranodal natural-killer T-cell lymphoma: a prospective cohort study from the international T-cell Project.Lancet Haematol2020;7:e284-94

[13] HuangY,deLeval L.Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type.Blood2010;115:1226-37 PMCID:PMC2826234

[14] Montes-MojarroIA,Ramirez-IbarguenAF.Mutational profile and EBV strains of extranodal NK/T-cell lymphoma, nasal type in Latin America.Mod Pathol2020;33:781-91

[15] LiZ,FengL.Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study.Lancet Oncol2016;17:1240-7 PMCID:PMC6790270

[16] LinG,ChenK.Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study in multiple populations.Lancet Oncol2020;21:306-16

[17] PengRJ,CaiQQ.Genomic and transcriptomic landscapes of Epstein-Barr virus in extranodal natural killer T-cell lymphoma.Leukemia2019;33:1451-62 PMCID:PMC6756073

[18] XiongJ,WangN.Genomic and transcriptomic characterization of natural killer T cell lymphoma.Cancer Cell2020;37:403-419.e6

[19] LeeSH,TisdaleS,LeslieCS.Widespread intronic polyadenylation inactivates tumour suppressor genes in leukaemia.Nature2018;561:127-31 PMCID:PMC6527314

[20] WeinholdN,RascheL.Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma.Blood2016;128:1735-44 PMCID:PMC5043128

[21] DongG,LeeL.Genetic manipulation of primary human natural killer cells to investigate the functional and oncogenic roles of PRDM1.Haematologica2021;106:2427-38 PMCID:PMC8409030

[22] KalliesA,HuntingtonND.A role for Blimp1 in the transcriptional network controlling natural killer cell maturation.Blood2011;117:1869-79

[23] KarubeK,TsuzukiS.Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses.Blood2011;118:3195-204

[24] KüçükC,HuX.PRDM1 is a tumor suppressor gene in natural killer cell malignancies.Proc Natl Acad Sci U S A2011;108:20119-24 PMCID:PMC3250125

[25] DesmotsF,PangaultC.Pan-HDAC inhibitors restore PRDM1 response to IL21 in CREBBP-mutated follicular lymphoma.Clin Cancer Res2019;25:735-46

[26] KimBR,JeongYA.RUNX3 enhances TRAIL-induced apoptosis by upregulating DR5 in colorectal cancer.Oncogene2019;38:3903-18

[27] HaiderA,UllmannR.Inactivation of RUNX3/p46 promotes cutaneous T-Cell lymphoma.J Invest Dermatol2016;136:2287-96

[28] ChisholmKM,BacchiCE,CherryA.Expression profiles of MYC protein and MYC gene rearrangement in lymphomas.Am J Surg Pathol2015;39:294-303

[29] NgSB,HuangG.Activated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling.J Pathol2011;223:496-510

[30] SelvarajanV,NahGSS.RUNX3 is oncogenic in natural killer/T-cell lymphoma and is transcriptionally regulated by MYC.Leukemia2017;31:2219-27 PMCID:PMC5629367

[31] ChenXJ,ChenB.Homoharringtonine deregulates.MYC116:2220-5 PMCID:PMC6369765

[32] JinJ,ChenF.Homoharringtonine-based induction regimens for patients with de-novo acute myeloid leukaemia: a multicentre, open-label, randomised, controlled phase 3 trial.Lancet Oncol2013;14:599-608

[33] YanJ,TayJL.EZH2 overexpression in natural killer/T-cell lymphoma confers growth advantage independently of histone methyltransferase activity.Blood2013;121:4512-20

[34] McCabeMT,GanjiG.EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations.Nature2012;492:108-12

[35] MorinRD,SeversonTM.Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin.Nat Genet2010;42:181-5 PMCID:PMC2850970

[36] YanJ,LinB.EZH2 phosphorylation by JAK3 mediates a switch to noncanonical function in natural killer/T-cell lymphoma.Blood2016;128:948-58

[37] LiB,PhyuT.MELK mediates the stability of EZH2 through site-specific phosphorylation in extranodal natural killer/T-cell lymphoma.Blood2019;134:2046-58

[38] ItalianoA,ToulmondeM.Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study.Lancet Oncol2018;19:649-59

[39] PatmoreDM,NathanE.DDX3X suppresses the susceptibility of hindbrain lineages to medulloblastoma.Dev Cell2020;54:455-470.e5 PMCID:PMC7483908

[40] PhungB,SannaA.The X-Linked DDX3X RNA helicase dictates translation reprogramming and metastasis in melanoma.Cell Rep2019;27:3573-3586.e7

[41] DobashiA,AsakaR.Frequent BCOR aberrations in extranodal NK/T-Cell lymphoma, nasal type.Genes Chromosomes Cancer2016;55:460-71

[42] JiangL,YanZX.Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma.Nat Genet2015;47:1061-6

[43] ChoiS,KimEK.Mutational analysis of extranodal NK/T-Cell lymphoma using targeted sequencing with a comprehensive cancer panel.Genomics Inform2016;14:78-84 PMCID:PMC5056900

[44] ChenQ,WuJ.HKDC1 C-terminal based peptides inhibit extranodal natural killer/T-cell lymphoma by modulation of mitochondrial function and EBV suppression.Leukemia2020;34:2736-48 PMCID:PMC7515829

[45] SongTL,LaurensiaY.Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma.Blood2018;132:1146-58 PMCID:PMC6148343

[46] LeeS,KangSY.Genetic alterations of JAK/STAT cascade and histone modification in extranodal NK/T-cell lymphoma nasal type.Oncotarget2015;6:17764-76 PMCID:PMC4627344

[47] CoppoP,HuangY.STAT3 transcription factor is constitutively activated and is oncogenic in nasal-type NK/T-cell lymphoma.Leukemia2009;23:1667-78 PMCID:PMC2796333

[48] ChenYW,ShenL.Receptor-type tyrosine-protein phosphatase κ directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma.Blood2015;125:1589-600

[49] BouchekiouaA,deWever O.JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma.Leukemia2014;28:338-48

[50] KooGC,TangT.Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma.Cancer Discov2012;2:591-7

[51] SimSH,KimTM.Novel JAK3-activating mutations in extranodal NK/T-cell lymphoma, nasal type.Am J Pathol2017;187:980-6

[52] NairismägiM-,LiZM.Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma.Leukemia2018;32:1147-56 PMCID:PMC5940653

[53] JostPJ.Aberrant NF-kappaB signaling in lymphoma: mechanisms, consequences, and therapeutic implications.Blood2007;109:2700-7

[54] SunL,ShiH,WeiL.LMP1 promotes nasal NK/T-cell lymphoma cell function by eIF4E via NF-κB pathway.Oncol Rep2015;34:3264-71

[55] SunL,ShiH,WeiL.LMP-1 induces survivin expression to inhibit cell apoptosis through the NF-κB and PI3K/Akt signaling pathways in nasal NK/T-cell lymphoma.Oncol Rep2015;33:2253-60

[56] BiXW,ZhangWW.PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma.J Hematol Oncol2016;9:109 PMCID:PMC5064887

[57] PiccalugaPP,AgostinelliC.Platelet-derived growth factor alpha mediates the proliferation of peripheral T-cell lymphoma cells via an autocrine regulatory pathway.Leukemia2014;28:1687-97

[58] IqbalJ,ChowdhuryA.International Peripheral T-cell Lymphoma ProjectNatural 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.Leukemia2011;25:348-58

[59] KawadaJ,IwataS.mTOR inhibitors induce cell-cycle arrest and inhibit tumor growth in Epstein-Barr virus-associated T and natural killer cell lymphoma cells.Clin Cancer Res2014;20:5412-22

[60] HuangD,NairismägiML.Evaluation of the PIK3 pathway in peripheral T-cell lymphoma and NK/T-cell lymphoma.Br J Haematol2020;189:731-44 PMCID:PMC7322801

[61] LeeWJ,LeeYJ.Vascular endothelial growth factor protein expression is associated with a poor prognosis in patients with cutaneous extranodal natural killer/T-cell lymphoma.Br J Dermatol2018;178:e11-2

[62] FearnleyGW,EdgarJR.The homophilic receptor PTPRK selectively dephosphorylates multiple junctional regulators to promote cell-cell adhesion.Elife2019;8:e44597 PMCID:PMC6440744

[63] ZhangL,O'SullivanM.The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers.Nat Med2007;13:1060-9

[64] SakoN,BagotM,SchmittC.HACE1, a potential tumor suppressor gene on 6q21, is not involved in extranodal natural killer/T-cell lymphoma pathophysiology.Am J Pathol2014;184:2899-907

[65] CimminoL,Ndiaye-LobryD.TET1 is a tumor suppressor of hematopoietic malignancy.Nat Immunol2015;16:653-62 PMCID:PMC4545281

[66] PooleCJ,ChoiJH.MYC deregulates TET1 and TET2 expression to control global DNA (hydroxy)methylation and gene expression to maintain a neoplastic phenotype in T-ALL.Epigenetics Chromatin2019;12:41 PMCID:PMC6604319

[67] LiL,MaoH.Epigenetic inactivation of the CpG demethylase TET1 as a DNA methylation feedback loop in human cancers.Sci Rep2016;6:26591 PMCID:PMC4880909

[68] GarzonR,CimminoA,CroceCM.MicroRNA expression and function in cancer.Trends Mol Med2006;12:580-7

[69] NgSB,HuangG.Dysregulated microRNAs affect pathways and targets of biologic relevance in nasal-type natural killer/T-cell lymphoma.Blood2011;118:4919-29

[70] WuSJ,WuB,GuoKY.MicroRNA-150 enhances radiosensitivity by inhibiting the AKT pathway in NK/T cell lymphoma.J Exp Clin Cancer Res2018;37:18 PMCID:PMC5793389

[71] KomabayashiY,NagatoT,TakaharaM.Downregulation of miR-15a due to LMP1 promotes cell proliferation and predicts poor prognosis in nasal NK/T-cell lymphoma.Am J Hematol2014;89:25-33

[72] PaikJH,JeonYK.MicroRNA-146a downregulates NFκB activity via targeting TRAF6 and functions as a tumor suppressor having strong prognostic implications in NK/T cell lymphoma.Clin Cancer Res2011;17:4761-71

[73] LiangL,ZhangS.The downregulation of PRDM1/Blimp-1 is associated with aberrant expression of miR-223 in extranodal NK/T-cell lymphoma, nasal type.J Exp Clin Cancer Res2014;33:7 PMCID:PMC3898819

[74] YamanakaY,TakahashiN.Aberrant overexpression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lymphoma/leukemia.Blood2009;114:3265-75

[75] BaytakE,AkmanB,ChanWC.Whole transcriptome analysis reveals dysregulated oncogenic lncRNAs in natural killer/T-cell lymphoma and establishes MIR155HG as a target of PRDM1.Tumour Biol2017;39:1010428317701648

[76] WangL,WangHN.LncRNA BCYRN1-induced autophagy enhances asparaginase resistance in extranodal NK/T-cell lymphoma.Theranostics2021;11:925-40 PMCID:PMC7738865

[77] LiuQ,WuZ.Long Non-coding RNA X-inactive specific transcript mediates cell proliferation and intrusion by modulating the miR-497/Bcl-w axis in extranodal natural killer/T-cell lymphoma.Front Cell Dev Biol2020;8:599070 PMCID:PMC7753184

[78] ZhuL,FuX.c-Myc mediated upregulation of long noncoding RNA SNHG12 regulates proliferation and drug sensitivity in natural killer/T-cell lymphoma.J Cell Biochem2019;120:12628-37

[79] KeirME,FreemanGJ.PD-1 and its ligands in tolerance and immunity.Annu Rev Immunol2008;26:677-704

[80] IwaiY,TanakaY,HonjoT.Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.Proc Natl Acad Sci U S A2002;99:12293-7 PMCID:PMC129438

[81] AnsellSM,BorrelloI.PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma.N Engl J Med2015;372:311-9 PMCID:PMC4348009

[82] HerbstRS,KimD.Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.Lancet2016;387:1540-50

[83] LarkinJ,GonzalezR.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med2015;373:23-34 PMCID:PMC5698905

[84] AndréT,KimTW.KEYNOTE-177 InvestigatorsPembrolizumab in microsatellite-instability-high advanced colorectal cancer.N Engl J Med2020;383:2207-18

[85] KwongYL,TanD.PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase.Blood2017;129:2437-42

[86] LiX,ZhangM.Activity of pembrolizumab in relapsed/refractory NK/T-cell lymphoma.J Hematol Oncol2018;11:15 PMCID:PMC5793390

[87] LimJQ,TangT.Whole-genome sequencing identifies responders to Pembrolizumab in relapse/refractory natural-killer/T cell lymphoma.Leukemia2020;34:3413-9 PMCID:PMC7685978

[88] KimSJ,LaurensiaY.Avelumab for the treatment of relapsed or refractory extranodal NK/T-cell lymphoma: an open-label phase 2 study.Blood2020;136:2754-63

[89] ShenX.Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis.BMJ2018;362:k3529 PMCID:PMC6129950

[90] KannoH,LiT,NakatsukaS.Low frequency of HLA-A*0201 allele in patients with Epstein-Barr virus-positive nasal lymphomas with polymorphic reticulosis morphology.Int J Cancer2000;87:195-9

[91] TianXP,YoungKH.A composite single-nucleotide polymorphism prediction signature for extranodal natural killer/T-cell lymphoma.Blood2021:452-63

[92] CohenJI.Epstein-Barr virus infection.N Engl J Med2000;343:481-92

[93] YoungLS,MurrayPG.Epstein-Barr virus: more than 50 years old and still providing surprises.Nat Rev Cancer2016;16:789-802

[94] ChiangAK,SrivastavaG.Nasal NK- and T-cell lymphomas share the same type of Epstein-Barr virus latency as nasopharyngeal carcinoma and Hodgkin's disease.Int J Cancer1996;68:285-90

[95] XuZG,OyamaN.The latency pattern of Epstein-Barr virus infection and viral IL-10 expression in cutaneous natural killer/T-cell lymphomas.Br J Cancer2001;84:920-5 PMCID:PMC2363835

[96] KangMS.Epstein-Barr virus latent genes.Exp Mol Med2015;47:e131 PMCID:PMC4314583

[97] HummeS,FeederleR.The EBV nuclear antigen 1 (EBNA1) enhances B cell immortalization several thousandfold.Proc Natl Acad Sci U S A2003;100:10989-94 PMCID:PMC196914

[98] OkunoY,SatoY.Defective Epstein-Barr virus in chronic active infection and haematological malignancy.Nat Microbiol2019;4:404-13

[99] NagamineM,KishibeK.Sequence variations of Epstein-Barr virus LMP1 gene in nasal NK/T-cell lymphoma.Virus Genes2007;34:47-54

[100] MenonV.XLF/Cernunnos: An important but puzzling participant in the nonhomologous end joining DNA repair pathway.DNA Repair (Amst)2017;58:29-37 PMCID:PMC6685063

[101] BauerCC,Popow-KrauppT,HofmannH.Serum Epstein-Barr virus DNA load in primary Epstein-Barr virus infection.J Med Virol2005;75:54-8

[102] ZhangY,TakakuT,OhyashikiK.Transcriptional profiling of Epstein-Barr virus (EBV) genes and host cellular genes in nasal NK/T-cell lymphoma and chronic active EBV infection.Br J Cancer2006;94:599-608 PMCID:PMC2361178

[103] NakhoulH,WangX,DongY.High-throughput sequence analysis of peripheral T-Cell lymphomas indicates subtype-specific viral gene expression patterns and immune cell microenvironments.mSphere2019;4:e00248-19 PMCID:PMC6620372

[104] QiuJ.EBV microRNA BART 18-5p targets MAP3K2 to facilitate persistence in vivo by inhibiting viral replication in B cells.Proc Natl Acad Sci U S A2014;111:11157-62 PMCID:PMC4121837

[105] IizasaH,AllaNR.Editing of Epstein-Barr virus-encoded BART6 microRNAs controls their dicer targeting and consequently affects viral latency.J Biol Chem2010;285:33358-70 PMCID:PMC2963350

[106] JungYJ,KimH.MicroRNA miR-BART20-5p stabilizes Epstein-Barr virus latency by directly targeting BZLF1 and BRLF1.J Virol2014;88:9027-37 PMCID:PMC4136301

[107] BollardCM,TorranoV.Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins.J Clin Oncol2014;32:798-808 PMCID:PMC3940538

[108] McLaughlinLP,GottschalkS.EBV/LMP-specific T cells maintain remissions of T- and B-cell EBV lymphomas after allogeneic bone marrow transplantation.Blood2018;132:2351-61 PMCID:PMC6265652

[109] AndoM,YamazakiS.Long-term eradication of extranodal natural killer/T-cell lymphoma, nasal type, by induced pluripotent stem cell-derived Epstein-Barr virus-specific rejuvenated T cells in vivo.Haematologica2020;105:796-807 PMCID:PMC7049350

[110] BurrML,ChanYC.CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity.Nature2017;549:101-5 PMCID:PMC5706633