title: Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression.
abstract: Prospective identification of patients whose chronic myeloid leukemia (CML) will progress to blast crisis is currently not possible. PP2A is a phosphatase and tumor suppressor that regulates cell proliferation, differentiation, and survival. Cancerous inhibitor of PP2A (CIP2A) is a recently described inhibitor of PP2A in breast and gastric cancer. The aim of this study was to investigate whether CIP2A played a role in CML and whether PP2A or its inhibitor proteins CIP2A or SET could predict clinical outcome. At the time of diagnosis of CML, patients who will later progress to blast crisis have significantly higher levels of CIP2A protein (P < .0001) than patients who do not progress, suggesting that PP2A is functionally inactive. We show that the potential mechanism for disease progression is via altered phosphorylation of the oncogene c-Myc. Knockdown of CIP2A results in increased PP2A activity, decreased c-Myc levels, and a decrease in BCR-ABL1 tyrosine kinase activity. We demonstrate that CIP2A levels at diagnosis can consistently predict patients who will progress to blast crisis. The data show that CIP2A is biologically and clinically important in CML and may be a novel therapeutic target.
authors.affiliation: Department of Haematology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Lucas
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Harris
authors.forename: Athina
authors.initials: A
authors.lastname: Giannoudis
authors.forename: Mhairi
authors.initials: M
authors.lastname: Copland
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Slupsky
authors.forename: Richard E
authors.initials: RE
authors.lastname: Clark
mesh_terms: D000328:Adult; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D001324:Autoantigens; D014408:Biomarkers, Tumor; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins