Genetic alterations of JAK/STAT cascade and histone modification in extranodal NK/T-cell lymphoma nasal type

Abstract

Extranodal NK/T-cell lymphoma nasal type (ENKL) is a rare type of non-Hodgkin lymphoma that more frequently occurs in East Asia and Latin America. Even though its molecular background has been discussed in the last few years, the current knowledge does not explain the disease pathogenesis in most cases of ENKL. Here, we performed multiple types of next-generation sequencing on 34 ENKL samples, including wholeexome sequencing (9 cancer tissues and 4 cancer cell lines), targeted sequencing (21 cancer tissues), and RNA sequencing (3 cancer tissues and 4 cancer cell lines). Mutations were found most frequently in 3 genes, STAT3, BCOR, and MLL2 (which were present in 9, 7, and 6 cancer samples, respectively), whereas there were only 2 cases of JAK3 mutation. In total, JAK/STAT pathway-and histone modification-related genes accounted for 55.9% and 38.2% of cancer samples, respectively, and their involvement in ENKL pathogenesis was also supported by gene expression analysis. In addition, we provided 177 genes upregulated only in cancer tissues, which appear to be linked with angiocentric and angiodestructive growth of ENKL. In this study, we propose several novel driver genes of ENKL, and show that these genes and their functional groups may be future therapeutic targets of this disease.

Frequent Mutations in Natural Killer/T Cell Lymphoma

“…Another study of a Chinese population revealed an similar frequency of 12% (three of 25) [65]. This frequency was found to be higher in Korea (26.4%, nine of 34) [66] and slightly lower in Japan (8%, two of 25) [18]. STAT3 mutations were found to occur at several (Fig.…”

“…STAT3 mutations were found to occur at several (Fig. 5) [18,66]. Previous studies revealed mutational hot spots in large granular lymphocytic leukemia, including Y640F in 13 (17%) cases, D661V in seven (9%), D661Y in seven (9%), and N647I in three (4%) [67].…”

“…The SH2B adaptor protein 3 (SH2B3) encodes a negative regulator of cytokine signaling, the loss of which also intrinsically increases STAT3 phosphorylation [70]. Additionally, PIK3R3, a downstream element of the JAK/STAT cascade that mediates cell proliferation, was found to be upregulated in all ENKL samples with STAT3 mutation [71]. All these factors, together with mutations in JAK3 and STAT3, or each independently, might play crucial roles in the initiation of NKTCL.…”

EZH2 phosphorylation by JAK3 mediates a switch to noncanonical function in natural killer/T-cell lymphoma

“…Our results are consistent with reports showing that most NKTL expressed phosphorylated JAK3 regardless of their JAK3 mutation status, 9 and several gene sets related to the PRC2 complex were enriched among these upregulated genes. 21 Conversely, phosphorylated EZH2 associates with Pol II at the promoters of noncanonical target genes and "actively" regulate the expression of these genes. We further elucidated that the phosphorylation of Y244 residue on EZH2 is the key molecular mediator of this switch between the PRC2-mediated canonical function of repressing polycomb group-target genes and the noncanonical function of transcriptional activation of distinct genes mediated via EZH2's association with transcriptional complex.…”

New developments in the pathology of malignant lymphoma. A review of the literature published from January 2014–April 2014

“…These findings indicate that primary DLBCL of the CNS genetically differs from DLBCL from other sites, but that there are also commonly affected pathways. A similar approach (using large amounts of data from multiple approaches on a rare tumour) was taken by Lee et al [3] for 34 cases of extranodal NK/T cell lymphoma nasal type (ENKL). They performed multiple types of next-generation sequencing, including WES (9 cancer tissues and 4 cancer cell lines), targeted sequencing (21 cancer tissues) and RNA sequencing (3 cancer tissues and 4 cancer cell lines).…”