Diagnostic and Biological Significance of KIR Expression Profile Determined by RNA-Seq in Natural Killer/T-Cell Lymphoma

Abstract

Natural killer/T-cell lymphoma (NKTCL) is a rare, aggressive form of non-Hodgkin lymphoma that is generally incurable at more advanced stages with systemic involvement. Clonal diagnostic markers (eg, unique T-or B-cell receptor rearrangements) are not available for NKTCLs. Killer cell immunoglobulin like receptors (KIRs) are a family of type I transmembrane glycoproteins involved in the inhibition or activation of NK cells. A restricted expression profile of KIRs has been proposed as clonal markers of NK-cell proliferations. Here we evaluated the transcription profile of all KIR family genes and C-type lectin receptor genes using RNA sequencing on NKTCL cases (n Z 17) and NK-cell lines (n Z 3). The expression of all KIRs tended to be markedly reduced or absent in NKTCL, except for the KIR family member killer Ig-like receptor 2DL4 (KIR2DL4; alias CD158D), which was selectively overexpressed in the majority (59%) of cases. No specific expression pattern was observed for C-type lectin receptors. KIR2DL4 is an unusual member of the KIR family that recognizes human leukocyte antigen G and mediates NK-cell activation through inducing proliferation and survival pathways such as AKT and NF-kB. Stable knockdown of KIR2DL4 in two malignant NK-cell lines with high KIR2DL4 expression significantly reduced cell growth. Selective overexpression of KIR2DL4 and downregulation of inhibitory KIRs may contribute to NKTCL pathogenesis. (Am J Pathol 2016, 186: 1435e1441; http://dx

Killer Immunoglobulin-Like Receptor 2DL4 (CD158d) Regulates Human Mast Cells both Positively and Negatively: Possible Roles in Pregnancy and Cancer Metastasis

“…In contrast, we observed that the KIR2DL4 protein expression was lacking in the human neoplastic mast cell line HMC1.2 expressing mutated KIT and deficient in FcεRI expression [52], and that nine of 15 cutaneous mastocytosis samples were KIR2DL4-negative [30]. These observations suggest that a lack of KIR2DL4 protein expression could serve as a diagnostic marker of neoplastic changes in mast cells, as is the case that lack of or decreased expression of KIR2DL4 is detected in neoplastic NK cells, NK cell lymphoma [53,54].…”

<p>DNA Methyltransferase Inhibitors: Catalysts For Antitumour Immune Responses</p>

“…In the tumour microenvironment, modification of the DNA regulatory sequences of KIR by hypermethylation is a common tumour escape mechanism. Therefore, promoting the expression of KIR using DNMTi would be an effective approach for cancer immunotherapy 103. Some studies104 have shown that the development and function of immune cells are regulated by DNA methylation.…”

Advances in multiple omics of natural-killer/T cell lymphoma

“…As for individual genes, it is noteworthy that MYC induces upregulation of EZH2 and RUNX3 , both of which exert cascade effect of transcriptional activation during lymphomagenesis [ 36 , 37 ]. Using RNA sequencing technology, overexpression of KIR2DL4 is reported in malignant NK cells [ 38 ]. KIR2DL4 mediates NK-cell activation via inducing proliferation and survival pathways such as NF-κB and AKT, which may contribute to NKTCL pathogenesis [ 38 ].…”

“…Using RNA sequencing technology, overexpression of KIR2DL4 is reported in malignant NK cells [ 38 ]. KIR2DL4 mediates NK-cell activation via inducing proliferation and survival pathways such as NF-κB and AKT, which may contribute to NKTCL pathogenesis [ 38 ].…”