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FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome–positive acute lymphocytic leukemia
Paolo Neviani, … , John C. Byrd, Danilo Perrotti
Paolo Neviani, … , John C. Byrd, Danilo Perrotti
Published September 4, 2007
Citation Information: J Clin Invest. 2007;117(9):2408-2421. https://doi.org/10.1172/JCI31095.
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Research Article Hematology

FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome–positive acute lymphocytic leukemia

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Abstract

Blast crisis chronic myelogenous leukemia (CML-BC) and Philadelphia chromosome–positive (Ph1-positive) acute lymphocytic leukemia (ALL) are 2 fatal BCR/ABL-driven leukemias against which Abl kinase inhibitors fail to induce a long-term response. We recently reported that functional loss of protein phosphatase 2A (PP2A) activity is important for CML blastic transformation. We assessed the therapeutic potential of the PP2A activator FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride), an immunomodulator in Phase III trials for patients with multiple sclerosis or undergoing organ transplantation, in CML-BC and Ph1 ALL patient cells and in in vitro and in vivo models of these BCR/ABL+ leukemias. Our data indicate that FTY720 induces apoptosis and impairs clonogenicity of imatinib/dasatinib-sensitive and -resistant p210/p190BCR/ABL myeloid and lymphoid cell lines and CML-BCCD34+ and Ph1 ALLCD34+/CD19+ progenitors but not of normal CD34+ and CD34+/CD19+ bone marrow cells. Furthermore, pharmacologic doses of FTY720 remarkably suppress in vivo p210/p190BCR/ABL-driven [including p210/p190BCR/ABL (T315I)] leukemogenesis without exerting any toxicity. Altogether, these results highlight the therapeutic relevance of rescuing PP2A tumor suppressor activity in Ph1 leukemias and strongly support the introduction of the PP2A activator FTY720 in the treatment of CML-BC and Ph1 ALL patients.

Authors

Paolo Neviani, Ramasamy Santhanam, Joshua J. Oaks, Anna M. Eiring, Mario Notari, Bradley W. Blaser, Shujun Liu, Rossana Trotta, Natarajan Muthusamy, Carlo Gambacorti-Passerini, Brian J. Druker, Jorge Cortes, Guido Marcucci, Ching-Shih Chen, Nicole M. Verrills, Denis C. Roy, Michael A. Caligiuri, Clara D. Bloomfield, John C. Byrd, Danilo Perrotti

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Figure 1

Dose-dependent effects of FTY720 in BCR/ABL-transformed cells.

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Dose-dependent effects of FTY720 in BCR/ABL-transformed cells.
(A) Molec...
(A) Molecular structure of FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride). (B) Effect of different doses (0–20 μM) of FTY720 on cytokine-independent proliferation of 32D-p210BCR/ABL cells and IL-3–dependent proliferation of parental 32Dcl3 cells. (C) p210BCR/ABL tyrosine phosphorylation (αPY) and expression (αAbl) in 32D-p210BCR/ABL cells untreated and treated 6–36 hours with 2.5 μM FTY720 (left panel). Graph shows levels of phosphorylated BCR/ABL (expressed as arbitrary densitometric units normalized to Grb2 levels) in 32D-p210BCR/ABL cells treated for 36 hours with the indicated concentrations of FTY720. Right blot: p210BCR/ABL activity in 32D-p210BCR/ABL cells treated for 36 hours with FTY720 (0–2.5 μM).

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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