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Jiang et al. J Transl Genet Genom 2021;5:323-40 https://dx.doi.org/10.20517/jtgg.2021.21 Page 325

PRDM1
PRDM1 encodes Blimp, a transcription inhibitor of NK cell and T cell differentiation, and regulates the
[22]
proliferation and maturation of NK cells . As a tumor suppressor gene (TSG) located in the 6q21 region,
PRDM1 is inactivated due to mutation, promoter methylation, or deletion, with a low expression level in
NKTCL [23,24] . Inhibition or inactivation of PRDM1 is supposed to upregulate genes or pathways related to
[21]
proliferation and cell cycle regulation such as MYC and to downregulate the pro-apoptotic factor BIM .
The above indicates that PRDM1 may mediate malignant transformation of cells and be a potential genetic
target. A recent study found that pan-acetyltransferase inhibitor vorinostat might restore PRDM1 response
to IL21 through decreasing BCL6 bound to PRDM1 in follicular lymphoma (FL) cells . According to the
[25]
results from vorinostat on nonfunctional CREBBP, FL cells showed a significant increase in PRDM1
expression after IL21 exposure. The expression of PRDM1 might be an important response predictor for
pan-HDAC inhibitors on FL cells. However, whether agents that restore PRDM1 exert anti-tumor activity
in NKTCL is still to be explored.

RUNX3 and MYC
Runt-related transcription factor 3 (RUNX3) presents a bilateral significance in different tumor
backgrounds. It is overexpressed in colorectal cancer and could promote TRAIL-induced apoptosis exerting
[26]
anti-tumor effect . In cutaneous T-cell lymphoma, the re-expression of RUNX3 decreases tumor cell
survival and induces apoptosis, indicating that RUNX3 acts as tumor suppressor gene .
[27]
There are different degrees of expression of MYC in different types of lymphoma . Compared with NK
[28]
cells, MYC is highly expressed and activated in NKTCL. The inhibition of its target genes may be a possible
mechanism for it playing an important role in the development of NKTCL .
[29]

Selvarajan et al. demonstrated that RUNX3 is overexpressed and oncogenic in NKTCL. MYC is involved
[30]
in the positive transcriptional regulation of RUNX3 . JQ1, a small molecule inhibitor, may induce
[30]
apoptosis of NKTCL cell lines by inhibiting transcription of MYC and downregulating RUNX3, which
indicates that RUNX3 and MYC may be potential therapeutic targets in NKTCL . In addition,
[30]
homoharringtonine is considered to downregulate the expression of MYC via directly binding to NKRF, the
inhibitor of nuclear factor kappaB (NF-κB) . Relevant clinical trials have shown that homoharringtonine-
[31]
based induction regimens can significantly improve the complete remission (CR) rate and progression-free
[32]
survival of acute myeloid leukemia patients . The potential therapeutic implication of this reagent deserves
to be further explored in NKTCL.

EZH2
Enhancer of zeste homolog 2 (EZH2) is overexpressed in NKTCL and acts as oncogene in tumor
progression [33,34] . Previous studies have shown that EZH2 undergoes frequently somatic mutations in FL and
diffuse large B-cell lymphoma (DLBCL), resulting in dysregulation of epigenetic silence function of
[36]
methyltransferase . Interestingly, Yan et al. considered that EZH2, as a transcriptional activator,
[35]
promoted proliferation through regulation of cyclin D1 expression by a non-canonical pathway. JAK3
kinase inhibitor PF956980 can induce the arrest of EZH2 phosphorylation and block its non-canonical
[36]
pathway via limiting the growth advantage of NKTCL cells . A recent study found that MELK (maternal
embryonic leucine zipper kinase), which regulates the ubiquitination and turnover of EZH2, increased
[37]
EZH2 S220 phosphorylation and promoted stabilization of EZH2 protein in NKTCL . These studies
demonstrate a potential target role of EZH2, and a JAK3 inhibitor may be a prospective treatment option.
Additionally, a phase II clinical trial (Clinical Trial No. NCT01897571) about the EZH2 inhibitor
tazemetostat treating refractory/relapsed B-cell non-Hodgkin’s lymphoma patients is ongoing. Of note,