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The T cell immunoglobulin and mucin domain 3 (Tim-3) is a plasma membrane-associated receptor which is involved in a variety of biological responses in human immune cells. It is highly expressed in most acute myeloid leukaemia (AML) cells and therefore may serve as a possible target for AML therapy. However, its biochemical activities in primary human AML cells remain unclear. We therefore analysed the total expression and surface presence of the Tim-3 receptor in primary human AML blasts and healthy primary human leukocytes isolated from human blood. We found that Tim-3 expression was significantly higher in primary AML cells compared to primary healthy leukocytes. Tim-3 receptor molecules were distributed largely on the surface of primary AML cells, whereas in healthy leukocytes Tim-3 protein was mainly expressed intracellularly. In primary human AML blasts, both Tim-3 agonistic antibody and galectin-9 (a Tim- 3 natural ligand) significantly upregulated mTOR pathway activity. This was in line with increased accumulation of hypoxia-inducible factor 1 alpha (HIF-1α) and secretion of VEGF and TNF-α. Similar results were obtained in primary human healthy leukocytes. Importantly, in both types of primary cells, Tim-3- mediated effects were compared with those induced by lipopolysaccharide (LPS) and stem cell factor (SCF). Tim-3 induced comparatively moderate responses in both AML cells and healthy leukocytes. However, Tim-3, like LPS, mediated the release of both TNF-α and VEGF, while SCF induced mostly VEGF secretion and did not upregulate TNF-α release.

// Vadim V. Sumbayev 1 , Isabel Goncalves Silva 1 , Jennifer Blackburn 1 , Bernhard F. Gibbs 1 , Inna M. Yasinska 1 , Michelle D. Garrett 2 , Alexander G. Tonevitsky 3 , Yuri A. Ushkaryov 1 1 School of Pharmacy, University of Kent, Chatham, Kent, ME4 4TB, United Kingdom 2 School of Biosciences, University of Kent, Canterbury, Kent, CT2 7NJ, United Kingdom 3 Hertsen Moscow Oncology Research Institute, Branch of The National Medical Research Radiological Center, Ministry of Health of The Russian Federation, 125284, Moscow, Russian Federation Correspondence to: Vadim V. Sumbayev, email: V.Sumbayev@kent.ac.uk Yuri A. Ushkaryov, email: Y.Ushkaryov@kent.ac.uk Keywords: latrophilin, myeloid leukaemia, mammalian target of rapamycin Received: March 17, 2016 Accepted: May 29, 2016 Published: June 14, 2016 ABSTRACT Acute myeloid leukaemia (AML) is a blood cancer affecting cells of myeloid lineage. It is characterised by rapid growth of malignant leukocytes that accumulate in the bone marrow and suppress normal haematopoiesis. This systemic disease remains a serious medical burden worldwide. Characterisation of protein antigens specifically expressed by malignant cells, but not by healthy leukocytes, is vital for the diagnostics and targeted treatment of AML. Here we report, for the first time, that the neuronal receptor latrophilin-1 is expressed in human monocytic leukaemia cell lines and in primary human AML cells. However, it is absent in healthy leukocytes. Latrophilin-1 is functional in leukaemia cells tested, and its biosynthesis is controlled through the mammalian target of rapamycin (mTOR), a master regulator of myeloid cell translational pathways. Our findings demonstrate that latrophilin-1 could be considered as a novel biomarker of human AML, which offers potential new avenues for AML diagnosis and treatment.