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Chronic Myeloproliferative Neoplasias

Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients

Leukemia volume 29, pages 1514–1523 (2015)Cite this article

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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.

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Acknowledgements

We thank our research nurses Katy Knight, Joanne Bell and Sarah Watmough for the provision of clinical samples.

Author contributions

CML performed experiments, designed the study and wrote the manuscript. AKH, EM, NC and LJS performed the experiments. FP advised on and performed the statistical analysis. RJH and REC designed the study and wrote the manuscript.

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Authors and Affiliations

  1. Department of Molecular and Clinical Cancer Medicine, Section of Haematology, University of Liverpool, Liverpool, UK

    C M Lucas, R J Harris, A K Holcroft, L J Scott, N Carmell, E McDonald & R E Clark

  2. CR-UK Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK,

    F Polydoros

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  1. C M Lucas
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Correspondence to R E Clark.

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REC has received research funding from Novartis, Bristol Myers Squibb, Pfizer Sanofi (not related to this publication), and is a member of the speakers bureau for Novartis and (not related to this publication) Sanofi. The remaining authors declare no conflict of interest.

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Lucas, C., Harris, R., Holcroft, A. et al. Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients. Leukemia 29, 1514–1523 (2015). https://doi.org/10.1038/leu.2015.71

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