Additional file 1: Supplemental Table S1. Characteristics of NKTL cell lines and culture conditions. Supplemental Table S2. The clinicopathological characteristics of these 3 NKTL patients. Supplemental Table S3. The list of primers and shRNA and their sequences. Supplemental Table S4. The list of SE-genes, RNA-seq overexpression genes and their common genes. Supplemental Table S5. shRNA screening identifies shared downregulated, upregulated genes affected by TOX2-shRNA1 and TOX2-shRNA2 in NKYS cell. Supplemental Table S6. TOX2 binding on 12 genes out of 65 genes downregulated by TOX-shRNA. Supplemental Table S7. Identification of TOX2 binding motif (^VSSSGVVGCG) in PTP4A3 promoter. Supplemental Table S8. RUNX3 binding motifs on TOX2-SE and their ChIP-PCR primers. Supplemental Table S9. Clinical features of 42 cases of NKTL and their expression of TOX2, RUNX3 and PRL-3 in CD3+ NKTL tumor cells. Figure S1. Determination of cell-origin of 3 NKTL cases on their RNA-seq data. This analysis was performed by using a two-sample Kolmogorov-Smirnov based method developed in house and the NK cell and T cell signature published by Xiong J, et al (Cancer Cell. 2020 Mar 16;37(3):403-419). This dot plot shows the genes expression of NK-origin (blue) and T-cells-origin (red). Lowly expressed genes (mean FPKM < 1) has been filtered out. Figure S2. UCSC Genome Browser ChIP-Seq screenshot. Track view of H3K27ac ChIP-seq density profile centered at the TBX21 (T-bet) and EOMES gene loci of NKTL cell line HNAK1 and NKYS (top panel), 3 tonsil controls (middle panel) and 3 primary NKTL patient samples (lower panel). Locations of the SEs regions were marked by red bars. Figure S3. Gene network of NKYS cells responding to TOX2 knockdown derived from GeneMANIA. A gene network from GeneMANIA shows the relationships for genes from the list of downregulated genes induced by TOX2-shRNAs according to the functional association networks from the databases. TOX2 sat on the top of the network and a physical interaction of network, indicated by a red arrow. Black rectangles highlight a few important targets, including PTP4A3, SPP1, SLAMF1, CD244, ITGB7. A black circle comprises some MHC family members. Figure S4. The expression of RUNX1 and RUNX3 in normal NK cells, NKTL cell lines and NKTL patient samples. Expression (lg2) level of RUNX1 and RUNX3 in a collection of normal NK cells, NKTL cell line and NKTL patient samples derived from a microarray dataset in Gene Expression Omnibus (GEO) database (accession number: GSE80632). p value < 0.05 is considered as statistically significant. Figure S5. TOX2 overexpression rescues NKYS cells from RUNX3 depletion. (A) Comparison of the rate of growth of co-transduced NKYS cells expressing FLAG-EV (empty vector) or FLAG-TOX2 and RUNX3-sh1 constructs. NKYS cells co-transduced with FLAG-EV and scramble shRNA were used as control. For each condition, cell number was counted at day 2, 4, and 6, then converted to fold change relative to the starting number at day 0. Same number of cells were seeded at day 0 and comparison was made at indicated days for relative fold changes. Three biologically independent experiments were performed (mean ± SD). Western blot analysis showing the expression of RUNX3 and TOX2 shown on the right. β-actin was used as the loading control.