Table 1.
Molecular pathogenesis of Epstein-Barr virus-positive NK/T-cell lymphoma.
| Molecular pathogenesis | Genetic alterations | Highlights | Target therapy |
|---|---|---|---|
| Chromosomal 6 abnormalities |
PRDM1 (47, 48) | Acts as both potential tumor suppressor and promoter. Hypermethylation of PRDM1 downregulated its expression and involved in the oncogenesis of ENKL. | |
| FOXO3 (25) | A tumor suppressor belonging to the fork-head family. | ||
| PTPRK (36) | The only protein tyrosine phosphatase at 6q that contains a STAT3-specifying motif. Loss of expression of PTPRK directly led to STAT3 activation and tumor progression in ENKL. | ||
| HACE1 (26) | A tumor suppressor, but it is not directly involved in the ENKL pathogenesis. | ||
| Gene mutations | DDX3X (30) | A tumor suppressor gene. DDX3X mutants reduced RNA-unwinding activity and deregulated suppressive effects on the NF-κB and MAPK pathways. | |
| ECSIT (24) | A gene associated with LAHPS. ECSIT-T419C mutants activated NF-κB signal pathway by binding with S100A8 and S100A9 heterodimer and enhanced the activity of NADPH oxidase inflammatory response. |
Dexamethasone and thalidomide | |
| Aberrant signaling pathways | JAK/STAT (33–35, 49, 50) | Acquired mutations (A573V, V722I, A572V, A573V, H583Y, and G589D) in the JAK3 pseudokinase domain resulted in constitutive JAK3 activation. STAT3 missense single-nucleotide variants (S614R, G618R, and A702T) and STAT5B missense mutation were located in the SH2 domain, which was critical for STAT activation and further promoted growth, survival and invasiveness of tumor cells. Constitutive JAK3 phosphorylation on tyrosine 980 was also involved in JAK3 activation. | JAK inhibitors CP-690550, PRN371 |
| NF-κB (24, 30, 51) | NF-κB was highly expressed in ENKL compared with normal NK cells. It was the key signaling pathway that was implicated in several genetic alterations, such as the overexpression of survivin, DDX3X mutants and LAHPS. | Bortezomib | |
| Deregulated single genes | Survivin (12, 37, 52) | Overexpression of survivin was detected in 97% of cases. And LMP-1 was proved to upregulate the expression of survivin through NF-κB and PI3K/Akt signaling pathways. | Terameprocol (EM-1421) |
| Myc (37, 40, 43) | Myc was highly expressed in the NK cell lines and tumor samples. Activation of myc was related to the upregulation of EZH2 and the overexpression of RUNX 3. | ||
| EZH2 (39, 40, 53) | EZH2 is a H3K27 methyltransferase that directly controls DNA methylation and silences several genes as a transcriptional repressor. It is also a “transcriptional activator” for driving oncogenesis. In ENKL, JAK3 could lead to the phosphorylation of EZH2 and resulted in the upregulation of several genes which were involved in DNA replication, cell cycle, and invasiveness. Also, the expression of EZH2 could be upregulated by myc by inducing repression of its regulatory microRNAs. | EZH2 inhibitor GSK126 | |
| RUNX3 (42, 43) | RUNX3 only shows oncogenic properties, but also acts as a tumor suppressor. myc transcriptional regulated RUNX3 by binding activity with it in NKTL. Inhibition of MYC could effectively inhibit RUNX3, following by increased apoptosis and reduced cell proliferation. | ||
| Epigenetic dysregulation | Hypermethylation (44) | Promoter hypermethylation is responsible for several suppressor genes being silenced, and those probably involved in ENKL are BCL2L11 (BIM), DAPK1, PTPN6 (SHP1), TET2, SOCS6, and ASNS. | |
| MicroRNA (46, 54, 55) | MicroRNAs, such as miR-101, miR26b, miR-26a, miR-28-5, and miR-363, were found dramatically downregulated in ENKL compared to normal NK cells. They functioned by regulating the expression of their predicted target genes. MiR-15a was reported to be downregulated by LMP-1. Besides, miR-146a could downregulate NF-κB activity by targeting TRAF6 and function as a tumor suppressor, which sequentially promote cell proliferation and predict poor prognosis. |