title: The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein.
abstract: The oncogenic BCR/ABL kinase activity induces and maintains chronic myelogenous leukemia (CML). We show here that, in BCR/ABL-transformed cells and CML blast crisis (CML-BC) progenitors, the phosphatase activity of the tumor suppressor PP2A is inhibited by the BCR/ABL-induced expression of the PP2A inhibitor SET. In imatinib-sensitive and -resistant (T315I included) BCR/ABL+ cell lines and CML-BC progenitors, molecular and/or pharmacological activation of PP2A promotes dephosphorylation of key regulators of cell proliferation and survival, suppresses BCR/ABL activity, and induces BCR/ABL degradation. Furthermore, PP2A activation results in growth suppression, enhanced apoptosis, restored differentiation, impaired clonogenic potential, and decreased in vivo leukemogenesis of imatinib-sensitive and -resistant BCR/ABL+ cells. Thus, functional inactivation of PP2A is essential for BCR/ABL leukemogenesis and, perhaps, required for blastic transformation.
authors.affiliation: Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Neviani
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Santhanam
authors.forename: Rossana
authors.initials: R
authors.lastname: Trotta
authors.forename: Mario
authors.initials: M
authors.lastname: Notari
authors.forename: Bradley W
authors.initials: BW
authors.lastname: Blaser
authors.forename: Shujun
authors.initials: S
authors.lastname: Liu
authors.forename: Hsiaoyin
authors.initials: H
authors.lastname: Mao
authors.forename: Ji Suk
authors.initials: JS
authors.lastname: Chang
authors.forename: Annamaria
authors.initials: A
authors.lastname: Galietta
authors.forename: Ashwin
authors.initials: A
authors.lastname: Uttam
authors.forename: Denis C
authors.initials: DC
authors.lastname: Roy
authors.forename: Mauro
authors.initials: M
authors.lastname: Valtieri
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bruner-Klisovic
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D001752:Blast Crisis / Q000378:metabolism*; D002461:Cell Line, Transformed; D002868:Chromosomal Proteins, Non-Histone / Q000502:physiology*; D005576:Colforsin / Q000494:pharmacology; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D056488:Histone Chaperones; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D020014:K562 Cells; D007938:Leukemia / Q000517:prevention & control; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D054648:Protein Phosphatase 2; D011743:Pyrimidines / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056488:Histone Chaperones; C432785:PPP2R1B protein, human; D010879:Piperazines; C086766:Ppp2r1b protein, mouse; D011743:Pyrimidines; C513473:SET protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D005576:Colforsin; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2