Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients
Open accessAbstract
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.
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The therapeutic effects of inhibition of CIP2A protein expression have been validated by numerous studies.
“This is a very important finding because the therapeutic effects of inhibition of CIP2A protein expression have been validated by numerous studies [6 -8,10 -12,21].”
From Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56 (2017) · cites this paper as [21]
CIP2A over-expression clinically correlates with relapse from kinase inhibitor therapies.
“CIP2A also broadly regulates cancer cell therapy responses, and its over-expression clinically correlates with relapse from kinase inhibitor therapies27–30.”
From Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A (2023) · cites this paper as [29]
CIP2A broadly regulates cancer cell therapy responses.
“CIP2A also broadly regulates cancer cell therapy responses, and its over-expression clinically correlates with relapse from kinase inhibitor therapies27–30.”
From Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A (2023) · cites this paper as [29]
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“The data show that the CIP2A(1-560) residues cross-linked to B56α are located primarily in the N-terminal head domain (K18, K21, E23, E34, K40) with an additional residue at the C-terminus (K490) (Fig.”
BackgroundMethodInfluential
- Authors
- Lucas, C. M., Harris, R. J., Holcroft, A. K., Scott, L. J., Carmell, N., McDonald, E., Polydoros, F., & Clark, R. E.
- Affiliations
- University of Liverpool (GB)
- Corresponding author
- Clark, R E
- Venue
- Leukemia
- Published
- 2015-03-13
- Volume
- 29
- Issue
- 7
- Pages
- 1514-1523
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- OpenAlex
- W1984551975
- Cited by
- 37
- References
- 54
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 1 · 2021: 4 · 2020: 1 · 2019: 4 · 2018: 7 · 2017: 5 · 2016: 3 · 2015: 1
- FWCI
- 4.19
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Leukemia (publishedVersion)
- PubMed (publishedVersion)
- ChesterRep (University of Chester) (submittedVersion, cc-by-nc-nd)
- Funders
- Cancer Research UK (15957)
- National Institute for Health and Care Research (MS-2010-007-303)
- Topics
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- chronic myeloid leukemia, CIP2A, second-generation tyrosine kinase inhibitors, imatinib, disease progression, protein phosphatase 2A, c-Myc, E2F1, BCR-ABL, positive feedback loop, K562 cells, CD34+ cells, prognostic factors
- MeSH terms
- Adult, Aged, Autoantigens, Female, Flow Cytometry, Follow-Up Studies, Humans, Male, Membrane Proteins, Middle Aged, Neoplasm Staging, Prognosis, Blotting, Western, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Survival Rate, Fusion Proteins, bcr-abl, Proto-Oncogene Proteins c-myc, Disease Progression, Drug Resistance, Neoplasm, RNA, Small Interfering, Protein Kinase Inhibitors, Intracellular Signaling Peptides and Proteins, Cell Proliferation, E2F1 Transcription Factor, Young Adult
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