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

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]

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