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

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 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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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.

Original languageEnglish (US)
Pages (from-to)2408-2421
Number of pages14
JournalJournal of Clinical Investigation
Volume117
Issue number9
DOIs
StatePublished - Sep 4 2007

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Blast Crisis
Philadelphia Chromosome
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Protein Phosphatase 2
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia
Immunologic Factors
Organ Transplantation
Myeloid Cells
Bone Marrow Cells
Multiple Sclerosis
Phosphotransferases
Therapeutics
Fingolimod Hydrochloride
Lymphocytes
Apoptosis
Cell Line
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

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FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. / Neviani, Paolo; Santhanam, Ramasamy; Oaks, Joshua J.; Eiring, Anna M.; Notari, Mario; Blaser, Bradley W.; Liu, Shujun; Trotta, Rossana; Muthusamy, Natarajan; Gambacorti-Passerini, Carlo; Druker, Brian; Cortes, Jorge; Marcucci, Guido; Chen, Ching Shih; Verrills, Nicole M.; Roy, Denis C.; Caligiuri, Michael A.; Bloomfield, Clara D.; Byrd, John C.; Perrotti, Danilo.

In: Journal of Clinical Investigation, Vol. 117, No. 9, 04.09.2007, p. 2408-2421.

Research output: Contribution to journalArticle

Neviani, P, Santhanam, R, Oaks, JJ, Eiring, AM, Notari, M, Blaser, BW, Liu, S, Trotta, R, Muthusamy, N, Gambacorti-Passerini, C, Druker, B, Cortes, J, Marcucci, G, Chen, CS, Verrills, NM, Roy, DC, Caligiuri, MA, Bloomfield, CD, Byrd, JC & Perrotti, D 2007, 'FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia', Journal of Clinical Investigation, vol. 117, no. 9, pp. 2408-2421. https://doi.org/10.1172/JCI31095
Neviani, Paolo ; Santhanam, Ramasamy ; Oaks, Joshua J. ; Eiring, Anna M. ; Notari, Mario ; Blaser, Bradley W. ; Liu, Shujun ; Trotta, Rossana ; Muthusamy, Natarajan ; Gambacorti-Passerini, Carlo ; Druker, Brian ; Cortes, Jorge ; Marcucci, Guido ; Chen, Ching Shih ; Verrills, Nicole M. ; Roy, Denis C. ; Caligiuri, Michael A. ; Bloomfield, Clara D. ; Byrd, John C. ; Perrotti, Danilo. / FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 9. pp. 2408-2421.
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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.",
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AU - Notari, Mario

AU - Blaser, Bradley W.

AU - Liu, Shujun

AU - Trotta, Rossana

AU - Muthusamy, Natarajan

AU - Gambacorti-Passerini, Carlo

AU - Druker, Brian

AU - Cortes, Jorge

AU - Marcucci, Guido

AU - Chen, Ching Shih

AU - Verrills, Nicole M.

AU - Roy, Denis C.

AU - Caligiuri, Michael A.

AU - Bloomfield, Clara D.

AU - Byrd, John C.

AU - Perrotti, Danilo

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N2 - 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.

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