Neviani P et al. (2007) FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome–positive acute lymphocytic leukemia. J Clin Invest 117: 2408–2421

Patients with blast crisis chronic myelogenous leukemia (CML) or adult acute lymphoblastic leukemias that express the BCR-ABL oncogene (Ph1-ALL) have a poor prognosis. CML typically starts with an indolent chronic phase followed by an aggressive myeloid or lymphoid blast crisis phase, which is dependent on the constitutive kinase activity of the BCR-ABL oncoprotein.

Imatinib, a BCR-ABL kinase inhibitor, shows excellent therapeutic efficacy in chronic-phase CML patients, but most patients with more-advanced CML or ALL do not show long-term response, or develop resistance, to imatinib and to the new generation of kinase inhibitors. Alternative treatments strategies are, therefore, required. Neviani et al. recently reported that a crucial point in blast transformation of CML is the loss of protein phosphatase 2A (PP2A) activity; they have subsequently investigated the therapeutic potential of the PP2A activator FTY720 (fingolimod) by use of BCR-ABL-transformed hematopoietic cell lines, primary bone marrow progenitors from chronic phase and blast crisis CML and Ph1-ALL patients sensitive and resistant to imatinib and/or dasatinib, and mouse models of these leukemias.

The study revealed that FTY720 induces cell death and reduces clonogenicity in myeloid and lymphoid cell lines and patient-derived progenitors that were either sensitive or resistant to imatinib and/or dasatinib, but it had no adverse effects on normal bone marrow progenitor cell growth and survival. Furthermore, pharmacological doses of FTY720 markedly suppressed the in vivo leukemogenesis driven by the wild-type and dasatinib-resistant T315I BCR-ABL oncogene kinases, without any observed toxicity in control animals. The authors conclude that rescuing PP2A tumor suppressor activity could be of great therapeutic relevance in patients with advanced-phase ALL or CML who are unresponsive to imatinib and/or dasatinib.