FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia.
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/p190(BCR/ABL) myeloid and lymphoid cell lines and CML-BC(CD34+) and Ph1 ALL(CD34+/CD19+) progenitors but not of normal CD34+ and CD34+/CD19+ bone marrow cells. Furthermore, pharmacologic doses of FTY720 remarkably suppress in vivo p210/p190(BCR/ABL)-driven [including p210/p190(BCR/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.
Neviani
Paolo
P
Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA.
Santhanam
Ramasamy
R
Oaks
Joshua J
JJ
Eiring
Anna M
AM
Notari
Mario
M
Blaser
Bradley W
BW
Liu
Shujun
S
Trotta
Rossana
R
Muthusamy
Natarajan
N
Gambacorti-Passerini
Carlo
C
Druker
Brian J
BJ
Cortes
Jorge
J
Marcucci
Guido
G
Chen
Ching-Shih
CS
Verrills
Nicole M
NM
Roy
Denis C
DC
Caligiuri
Michael A
MA
Bloomfield
Clara D
CD
Byrd
John C
JC
Perrotti
Danilo
D
D000818:Animals; D001549:Benzamides; D001752:Blast Crisis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D015394:Molecular Structure; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011409:Propylene Glycols / Q000737:chemistry / Q000627:therapeutic use*; D054648:Protein Phosphatase 2; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D001549:Benzamides; D010879:Piperazines; D011409:Propylene Glycols; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D000069439:Dasatinib
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