FTY720, a New and Alternative Strategy for Treating Blast Crisis CML and Ph1 ALL Patients.

Abstract Blast crisis chronic myelogenous leukemia (CML-BC) and Philadelphia chromosome positive (Ph1) acute lymphoblastic leukemia (ALL) are two fatal BCR/ABL-driven leukemias against which the current therapy with Abl kinase inhibitors fails to induce a long-term response, as the majority of patients are either refractory or relapse after a few months of treatment. We recently reported that functional loss of the PP2A tumor suppressor occurs during CML disease progression and that restoration of PP2A activity impairs in vitro and in vivo BCR/ABL leukemogenesis. Here we assessed the therapeutic potential of the PP2A activator FTY720 in CML-BC and Ph1 ALL patient cells and in in vitro and in vivo models of these BCR/ABL+ leukemias. FTY720 (500 nM-2.5 mM) induces caspase-dependent apoptosis (70–98% annexin V+) and impairs the clonogenic potential (70–95% inhibition) of imatinib/dasatinib-sensitive and -resistant (T315I) p210 and p190 BCR/ABL-expressing myeloid and lymphoid progenitor cell lines (Ph1 K562, 32D-p210BCR/ABL, 32D-p210(T315I)BCR/ABL and BaF3-p190BCR/ABL), respectively, and of primary bone marrow CML-BCCD34+ (n=11) and Ph1 ALLCD34+/CD19+ (n=12) patients cells. Interestingly the cytokine (IL-3 or IL-7)-dependent growth and differentiation of normal CD34+ myeloid and CD34+/CD19+ lymphoid progenitors (n=8) is not affected by FTY720 treatment. Furthermore, pharmacologic doses of FTY720 markedly suppress leukemogenesis in SCID mice (n=13 per group) transplanted with myeloid and lymphoid progenitor cells transformed with p210BCR/ABL and p190BCR/ABL, respectively. In fact, the median survival has not yet been reached in FTY720-treated (10 mg/kg/day) BCR/ABL+ cell-injected mice. Conversely, all of untreated 32D-p210BCR/ABL, 32D-p210BCR/ABL(T315I) and BaF3-p190BCR/ABL leukemic mice died of an overt acute leukemia-like process with a median survival of 4.3, 4.8 and 4.1 weeks, respectively (P<0.001). After 11 weeks of FTY720 treatment, 80% and 90% of p210 and p190 mice, respectively, were alive and in molecular remission. Moreover, long-term (189 days) FTY720 daily administration (10 mg/kg/day) did not induce any adverse effect, and achieved sustained absence of BCR/ABL+ cells (assessed by nested RT-PCR) in 50% of mice transplanted with myeloid progenitors expressing the imatinib/dasatinib-resistant T315I p210BCR/ABL mutant. Mechanistically, the anti-leukemic effects of FTY720 are sphingosine 1-phosphate receptor 1 (SIP1)-mediated and dependent on the ability of FTY720 to activate PP2A phosphatase. That, in turn, inhibits the activity and expression of wild type and mutant p210 and p190 BCR/ABL oncoproteins and important regulators (e.g. Akt) of malignant cell survival and proliferation. Altogether, these results not only reinforce the importance of the PP2A tumor suppressor in the biology of Ph1 leukemias but, because FTY720 has been shown to be feasible in Phase I-III clinical trials for multiple sclerosis or solid organ transplant patients, they strongly support the use of this PP2A activator as a novel therapeutic approach for CML-BC and Ph1 ALL.

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