title: Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients.
abstract: High cancerous inhibitor of PP2A (CIP2A) protein levels at diagnosis of chronic myeloid leukaemia (CML) are predictive of disease progression in imatinib-treated patients. It is not known whether this is true in patients treated with second generation tyrosine kinase inhibitors (2G TKI) from diagnosis, and whether 2G TKIs modulate the CIP2A pathway. Here, we show that patients with high diagnostic CIP2A levels who receive a 2G TKI do not progress, unlike those treated with imatinib (P=<0.0001). 2G TKIs induce more potent suppression of CIP2A and c-Myc than imatinib. The transcription factor E2F1 is elevated in high CIP2A patients and following 1 month of in vivo treatment 2G TKIs suppress E2F1 and reduce CIP2A; these effects are not seen with imatinib. Silencing of CIP2A, c-Myc or E2F1 in K562 cells or CML CD34+ cells reactivates PP2A leading to BCR-ABL suppression. CIP2A increases proliferation and this is only reduced by 2G TKIs. Patients with high CIP2A levels should be offered 2G TKI treatment in preference to imatinib. 2G TKIs disrupt the CIP2A/c-Myc/E2F1 positive feedback loop, leading to lower disease progression risk. The data supports the view that CIP2A inhibits PP2Ac, stabilising E2F1, creating a CIP2A/c-Myc/E2F1 positive feedback loop, which imatinib cannot overcome.
authors.affiliation: Section of Haematology, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Lucas
authors.affiliation: Section of Haematology, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: R J
authors.initials: RJ
authors.lastname: Harris
authors.affiliation: Section of Haematology, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: A K
authors.initials: AK
authors.lastname: Holcroft
authors.affiliation: Section of Haematology, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: L J
authors.initials: LJ
authors.lastname: Scott
authors.affiliation: Section of Haematology, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: N
authors.initials: N
authors.lastname: Carmell
authors.affiliation: Section of Haematology, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: E
authors.initials: E
authors.lastname: McDonald
authors.affiliation: CR-UK Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK.
authors.forename: F
authors.initials: F
authors.lastname: Polydoros
authors.affiliation: Section of Haematology, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: R E
authors.initials: RE
authors.lastname: Clark
mesh_terms: D000328:Adult; D000368:Aged; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015996:Survival Rate; D055815:Young Adult
chemical_list: D001324:Autoantigens; C500266:CIP2A protein, human; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C489427:MYC protein, human; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D016044:Fusion Proteins, bcr-abl