NK cell Eradication of Residual Leukemic Cells in Chronic Myeloid Leukaemia

Abstract

Chronic myeloid leukaemia (CML) is a myeloproliferative disease driven by the fusion oncogene BCR-ABL, a tyrosine kinase involved in cell proliferation regulation. CML patients treated with tyrosine kinase inhibitor (TKI) therapy have a life expectancy comparable with the healthy population, and their quality of life is near normal. However, some patients experience side effects, which is one of the reasons why TKI discontinuation attempts have been made for CML patients in complete molecular response (CMR), i.e. in remission. It has been observed that patients in treatment-free remission (TFR) have high levels of NK cells, and that expression of activating NK cell receptors are correlated with leukaemia-free survival and overall survival in patients with other myeloproliferative leukaemias. In this thesis work we evaluated the expression of activating NK cell receptors and their ligands in peripheral blood mononuclear cell (PBMC) samples from newly diagnosed CML patients in chronic phase. Several ligands were expressed, and the most interesting finding was that the expression of the DNAM-1-ligand Nectin-2 was higher in more immature (CD38-negative) CD34-positive CML blasts than in less immature (CD38-positive), whereas the expression was the opposite in the blast populations in the G-CSF treated healthy control. We used a robust cytotoxicity assay with co-cultures of expanded CML blasts and IL-2 stimulated polyclonal NK cells from a healthy donor to show that the activating NK cell receptors DNAM-1 and NKp30 have a role in the NK cell-mediated killing of CML cells.