Having shown that FTY720 suppresses the growth of BCR-ABL transformed cells in a dose-dependent manner, the authors used phosphatase assays to show that FTY720 restores the activity of PP2A and hampers the activity of BCR-ABL in imatinib sensitive and resistant CML-BC patient cells and in Ph1ALL patient cells. FTY720 treatment also decreased the phosphorylation, and thereby the activity, of the BCR-ABL and PP2A targets Akt, STAT5 and ERK1/2 in CML-BC and Ph1ALL cell lines. In addition, treatment with the serine-threonine phosphatase inhibitor okadaic acid at concentrations that specifically inhibit the activity of PP2A restored BCR-ABL activity and rescued PP2A target activity in FTY720-treated CML-BC cell lines.
So, what are the biological effects of treatment with FTY720? CD34+ leukaemic cells from patients and cell lines treated with FTY720 underwent caspase-dependent apoptosis, whereas normal CD34+ bone marrow donor cells were not affected. Even a single dose of FTY720 caused 70–98% suppression of clonogenic potential of CML-BC patient cells and leukaemic cell lines, and this was independent of whether the cells were resistant to imatinib (with the T315I mutation in BCR-ABL) or not. Moreover, long-term treatment with FTY720 suppressed leukaemogenesis without any adverse effects when using severe combined immunodeficiency (SCID) mouse models of CML-BC (imatinib sensitive or resistant) and Ph1ALL. 80–90% of treated leukaemic mice were BCR-ABL negative at 16 weeks, and all were still alive at 27 weeks after transplant. By contrast, the median survival of the untreated leukaemic mice was 4–5 weeks.
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