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Table 1 The key pathogenic pathways in ENKTL are described with a summary of the specific molecular/genetic abnormalities involved in each pathway. Evidence for each pathway as a therapeutic target is indicated where applicable

From: Molecular pathogenic pathways in extranodal NK/T cell lymphoma

Mechanism of Lymphomagenesis (Hallmarks of cancer) Specific pathway / target Role in Lymphoma Biology References Therapeutic Significance References
Sustaining proliferative signaling JAK/STAT Upregulated via mutation or phosphorylation Huang et al. [5, 80] Anti-tumor activity of JAK-3 and STAT-3 inhibition in pre-clinical / in vitro models. Clinical trials evaluating JAK inhibitors in ENKTL ongoing. Nairismagi et al. [24]
Sim et al. [19]
RUNX3 Upregulated and has oncogenic role promoting proliferation and survival in ENTKL. Selvarajan et al. [44] MYC inhibition in vitro leads to down-regulation of RUNX3 and apoptosis, suggesting MYC as potential therapeutic target. Selvarajan et al. [44]
EZH2 Upregulated and functions as a transcriptional co-activator via a non-canonical pathway. Yan et al. [27] Targeting EZH2 using a PCR2 inhibitor induces apoptosis in ENKTL. Yan et al. [28]
NF-kB Upregulated and promotes survival and proliferation. Huang et al. [5, 80] Bortezomib in ongoing early phase clinical trials for ENKTL. Liu et al. [32]
Ng et al. [7, 41] Tang et al [36]
Chen et al. [35]
AURKA Upregulated, promotes cell proliferation. Iqbal et al. [6] In vitro inhibition of AURKA induced apoptosis Iqbal et al. [6]
Ng et al. [7, 41]
PDGFRα Upregulated. Mediates migration, proliferation and cell survival. de Mel et al. [162] Potential therapeutic target for tyrosine kinase inhibitors. Huang et al. [5, 80]
NOTCH Upregulated in ENKTL, involved in developmental processes and cancer. Huang et al. [5, 80] Potential therapeutic target for NOTCH inhibitors. Aster et al. [163]
CDK2, HSPCA Upregulated. Promotes proliferation and survival of cancer cells. Zhang et al. [164] N/A N/A
DDX3X RNA helicase, loss of function mutations lead to cell cycle progression and activation of other pro-proliferative pathways Jiang et al [18] N/A N/A
Evading Growth Supressors /Resisting Cell Death Survivin Upregulated in the majority of ENKTL. Inhibits apoptosis. Ng et al. [7, 41] Survivin inhibition in vitro induced apoptosis, suggesting potential therapeutic role. Ng et al. [7, 41],
Ng et al. [165] de Mel et al. [162]
P53 Upregulated (e.g. by mutation). Inhibits apoptosis. Ng et al. [7, 41] N/A N/A
Quintanilla Martinez et al. [66]
BIRC1, IL-1A, TNFRS10D Upregulated, inhibits apoptosis. Zhang et al. [164] N/A N/A
PTPRK Frequently deleted and hypermethylated. Re expression suppressed proliferation and induced apoptosis. Precise function under evaluation   N/A N/A
PRDM1 Frequently deleted in and re expression leads to cell growth. Functional role under investigation.   N/A N/A
FOXO3 Frequently deleted in apoptosis induced by re-expression. Function under investigation   N/A N/A
HACE1 Encodes E3 ubiquitin ligase, frequently deleted and hypermethylated. Function Under investigation   N/A N/A
ATG5 Candidate tumour suppressor gene awaiting evaluation of function.   N/A N/A
AIM1 Candidate tumour suppressor gene awaiting evaluation of function.   N/A N/A
Autophagy pathway Beclin 1 under-expression is associated with a worse prognosis Huang et al. [5, 80] Response to HDAC inhibition in combination with bortezomib in two patients with RR ENKTL. Tan et al. [81]
Immune Evasion PD-L1 Upregulated. Involved in immune evasion. Ng et al. [3, 116] Patients with relapsed ENKTL showed response to pembrolizumab, an antibody against PD1. Kwong et al. [11]
de Mel et al. [162]
Genomic Instability/Deregulated DDR ATR Deregulation (e.g. deletion) resulting in abnormal DNA damage response. Liu et al. [123] N/A N/A
Angiogenesis VEGF Upregulated. Promotes tumour vascularization and growth. Jørgensen et al. [127], de Mel et al. [162] Potential therapeutic target. Jørgensen et al. [127]
Other Mechanisms and Targets
 Epigenetic Deregulation Promoter Hypermethylation Widespread promoter hypermethylation leading to down regulation of tumor suppressor genes. Kucuk et al. [20] N/A N/A
BCOR Interacts with HDAC family. Role in ENKTL under evaluation Huynh et al. [157] N/A N/A
MLL2 Histone methyltransferase. Role in ENKTL under evaluation Milne et al. [158] N/A N/A
miR-150 Downregulated of miRNAs in ENKTL. Targets of these miRNAs include genes in critical pathways such as p53, MAPK and EZH2 Ng et al. [7, 41] N/A N/A
miR-101
miR-26a
miR-26b
miR-28-5
miR-363
miR-146
miR-21 Upregulated and have a pro-oncogenic function Yamanaka et al. [59] N/A N/A
miR-155
miR-146a Downregulated, associated with poor prognosis Paik et al. [104] N/A N/A
miR-221 Upregulated, associated with poor prognosis. Guo et al. [166] N/A N/A
 EBV Mediated Mechanisms EBV lytic genes (BHRF1, BKRF3, BZLF1) Upregulated. Potential pathogenic role in ENKTL . BHRF1 may have anti-apoptotic role due to sequence homolog to human BCL-2. Zhang et al. [164] N/A N/A
 CD38 CD38 Upregulated. Exact role unknown but associated with poorer prognosis. Hu et al. [167] Good in-vitro efficacy of daratumumab and one case report documenting complete response. Mustafa et al. [153]
Hari et al. [154]
  1. Abbreviations: ENKTL Extranodal NK Tcell lymphoma, EBV Epstein Barr Virus, HDAC Histone deacetylase, RR Relapsed Refractory, N/A No available data to support a therapeutic role at present