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.
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Therapeutic impact of inhibition of CIP2A protein expression has been validated by numerous studies across human cancer types.
“therapeutic impact of inhibition of CIP2A protein expression has been validated by numerous studies across human cancer types18,20,21,23,33,34.”
From Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A (2023) · cites this paper as [20]
CIP2A is widely over-expressed in different human cancer types.
“Of these, CIP2A is widely over-expressed in different human cancer types and drives tumour growth both in xenograft and transgenic mouse models18–24.”
From Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A (2023) · cites this paper as [20]
CIP2A drives tumour growth in xenograft and transgenic mouse models.
“Of these, CIP2A is widely over-expressed in different human cancer types and drives tumour growth both in xenograft and transgenic mouse models18–24.”
From Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A (2023) · cites this paper as [20]
Among cancers, AML and CML are the only types in which CIP2A mRNA appears lower than in corresponding normal tissue.
“This is interesting, as AML and CML are the only cancer types in which CIP2A seems to be underexpressed at the mRNA level compared with corresponding normal tissue (Fig. 6I; refs.4,23).”
From Discovery of a Novel CIP2A Variant (NOCIVA) with Clinical Relevance in Predicting TKI Resistance in Myeloid Leukemias (2021) · cites this paper as [4]
CIP2A is overexpressed in many human cancers, and high CIP2A expression correlates with poor patient survival across a broad spectrum of malignancies.
“CIP2A is overexpressed in a vast variety of human cancers, and high CIP2A expression has been shown to correlate with poor patient survival in a broad spectrum of human malignancies (3)(4)(5)(6).”
From Discovery of a Novel CIP2A Variant (NOCIVA) with Clinical Relevance in Predicting TKI Resistance in Myeloid Leukemias (2021) · cites this paper as [4]
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Self-citationStructural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A
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Self-citation
- Authors
- Lucas, C. M., Harris, R. J., Giannoudis, A., Copland, M., Slupsky, J. R., & Clark, R. E.
- Affiliations
- University of Liverpool (GB)
- Gartnavel General Hospital (GB)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2011-06-16
- Volume
- 117
- Issue
- 24
- Pages
- 6660-6668
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2040802938
- Cited by
- 138
- References
- 35
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 2 · 2021: 13 · 2020: 6 · 2019: 12 · 2018: 4 · 2017: 10 · 2016: 18 · 2015: 16 · 2014: 10 · 2013: 20 · 2012: 11
- FWCI
- 9.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Funders
- University of Liverpool
- Topics
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- CIP2A, chronic myeloid leukemia, protein phosphatase 2A, sets, c-Myc phosphorylation, prognostic factors, disease progression, therapeutic target
- MeSH terms
- Adult, Autoantigens, Cells, Cultured, Female, Humans, Male, Membrane Proteins, Middle Aged, Prognosis, Biomarkers, Tumor, Cohort Studies, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Gene Expression Regulation, Leukemic, Survival Analysis, Disease Progression, K562 Cells, Intracellular Signaling Peptides and Proteins
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