Targeted therapy: Blast it away!
Reactivating the tumor-suppressor protein phosphatase 2A (PP2A) induces apoptosis in chronic myeloid leukemia-blast crisis and Philadelphia chromosome positive acute lymphocytic leukemia (Ph1ALL) cell lines, as well as in cells from patients.
The development and maintenance of chronic myeloid leukaemia (CML) and Philadelphia chromosome positive acute lymphocytic leukaemia (Ph1ALL) are driven by unrestrained kinase activity of the BCR-ABL oncoprotein. Most CML patients in blast crisis (CML-BC) and patients with Ph1ALL are refractory or develop resistance to ABL inhibitors, such as imatinib and dasatinib. Danilo Perrotti and colleagues now show that reactivating the tumour-suppressor protein phosphatase 2A (PP2A) using FTY720 induces apoptosis in CML-BC and Ph1ALL cell lines, and in cells from patients.
 |  |
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.
FTY720 is in clinical trials as an immunomodulator for multiple sclerosis and renal transplantation, and has been tested on solid tumours. However, this work showing that FTY720 interferes with BCR-ABL oncogenic activity and induces apoptosis in leukaemic cells at very low doses supports the investigation of this drug to treat CML-BC and Ph1ALL patients who have failed ABL inhibitor therapies.
Ezzie Hutchinson
References
- Neviani, P. et al. FTY720, a new alternative for treating blast crisis chronic myelogenous leukaemia and Philadelphia chromosome-positive acute lymphocytic leukaemia. J. Clin. Invest. 117 2408–2421 (2007) | Article | PubMed |
 more stories
| 
