SLAM family member 8 is involved in oncogenic KIT‐mediated signalling in human mastocytosis

Abstract

The signalling lymphocytic activation molecule family member 8 (SLAMF8)/CD353 is a member of the CD2 family of proteins. Its ligand has not been identified. SLAMF8 is expressed by macrophages and suppresses cellular functions. No study has yet explored SLAMF8 expression or function in human mastocytosis, which features oncogenic KIT-mediated proliferation of human mast cells. SLAMF8 protein was expressed in human mastocytosis cells, immunohistochemically. SLAMF8 expression was also evident in the human mast cell lines, HMC1.2 (expressing oncogenic KIT) and LAD2 (expressing wild-type KIT) cells. SLAMF8 knock-down significantly reduced the KIT-mediated growth of HMC1.2 cells but not that of LAD2 cells. SLAMF8 knock-down HMC1.2 cells exhibited significant attenuation of SHP-2 activation and oncogenic KIT-mediated RAS-RAF-ERK signalling. An interaction between SLAMF8 and SHP-2 was confirmed in HMC1.2 cells and all pathological mastocytosis specimens examined (19 of 19 cases, 100%). Thus, SLAMF8 is involved in oncogenic KIT-mediated RAS-RAF-ERK signalling and the subsequent growth of human neoplastic mast cells mediated by SHP-2. SLAMF8 is a possible therapeutic target in human mastocytosis patients.

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

“…Studies using mast cell-deficient mice, such as Kit W/Wv mice and Kit Wsh/Wsh mice, revealed that mast cells protect against parasitic infections including Strongyloides ratti and Strongyloides brasiliensis [7,8], as well as the venoms of honeybees or vipers [9]. Mast cells are (KIR) 2DL4 [19][20][21][22][23][24][25][26][27][28][29][30][31]. These include inhibitory receptors characterized by immunoreceptor tyrosine-based inhibitory motifs (ITIMs) within their cytosolic domains ( Figure 1) [32].…”

SLAM family member 8 is expressed in and enhances the growth of anaplastic large cell lymphoma

“…SLAMF8 suppresses the functions of human macrophages 5,6 but has an enhancing effect in human ALK-positive ALCL cell lines and in human KIT-mutated neoplastic mast cell lines 7 . We previously hypothesized that this difference was due to the differential expression of adaptor proteins between human macrophages and KIT-mutated neoplastic mast cells; specifically, human macrophages express the adaptor proteins, SAP and EAT-2, which interacting with SLAMF8 15 .…”

“…We previously hypothesized that this difference was due to the differential expression of adaptor proteins between human macrophages and KIT-mutated neoplastic mast cells; specifically, human macrophages express the adaptor proteins, SAP and EAT-2, which interacting with SLAMF8 15 . We are suspecting that these adaptor proteins interfere with the interaction between SHP-2 and SLAMF8 in human macrophage, and the absent expression of SAP and EAT-2 facilitate the interaction between SHP-2 and SLAMF8 in human neoplastic mast cells 7,16 . In this study, we observed SAP-2 and EAT-2 expression in ALK-positive ALCL cell lines (data not shown).…”

“…We assessed the status of signaling molecules in ALCL cell lines using an ELISA kit. SHP-2 plays a central role in the growth of ALCL cells 12 , and we previously reported that SHP-2 is important for SLAMF8-associated neoplastic mast cell growth 7 . Therefore, we assessed the status of SHP-2 in ALCL cells with SLAMF8 knockdown.…”

“…Both kits were used according to the manufacturer's instructions. Then we performed PCR using the primers 5′-CCCAACATCAGCGAAATAACC-3′ and 5′-GAAGAGAGTAACCAGCATCAG-3′ 7 . PCR was performed as follows: 94 °C at 5 min, followed by 28 cycles of 94 °C for 30 s, 61 °C for 30 s, and 72 °C for 30 s, and a final extension at 72 °C for 10 min.…”