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EVI1 upregulates PTGS1 (COX1) and decreases the action of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia cells

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Abstract

Tyrosine kinase inhibitors (TKIs) are highly effective in treating chronic myelogenous leukemia (CML). However, primary and acquired drug resistance to TKIs have been reported. In this study, we used RNA sequencing followed by RQ-PCR to show that the proto-oncogene EVI1 targets the drug-metabolizing gene PTGS1 in CML. The PTGS1 promoter element had an EVI1 binding site, and CHIP assay confirmed its presence. Data from a publicly available CML microarray dataset and an independent set of CML samples showed a significant positive correlation between EVI1 and PTGS1 expression in CML. Downregulation of EVI1 in K562 cells and subsequent treatment with TKIs resulted in a lower IC50 in the control cells. Furthermore, combined inhibition of BCR-ABL with imatinib and PTGS1 with FR122047 (PTGS1 inhibitor) synergistically reduced the viability of imatinib-resistant K562 cells. We conclude that elevated EVI1 expression contributes to TKIs resistance and that combined inhibition of PTGS1 and BCR-ABL may represent a novel therapeutic approach.

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Data availability

All the data are available on request to the corresponding author.

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Acknowledgements

The DST-SERB NPDF fellowship was awarded to Dr. Kittappa Vinothkumar funded the work (PDF/2017/000139). The work was also partly funded by two other SERB projects, EMR/2014/000318 and CRG/2019/003113, awarded to Dr. Soumen Chakraborty. Sayantan Chanda is supported by University Grants Commission and is registered for the Ph.D. program at the Regional Centre for Biotechnology, Faridabad. The Institute of Life Sciences supported Dr. Vivek Singh.

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Author notes

  1. Kittappa Vinothkumar and Sayantan Chanda contributed equally to this work.

Authors and Affiliations

  1. Cancer Biology Group, Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, India

    Kittappa Vinothkumar, Sayantan Chanda, Vivek Kumar Singh & Soumen Chakraborty

  2. Regional Centre for Biotechnology, Faridabad, Haryana, India

    Sayantan Chanda & Soumen Chakraborty

  3. Sparsh Hospital and Critical Care, Bhubaneswar, India

    Sutapa Biswas & Ghanashyam Biswas

  4. Department of Medical Oncology/Hematology, All India Institute of Medical Sciences, Bhubaneswar, India

    Sonali Mohapatra

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  1. Kittappa Vinothkumar
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Contributions

KVK, SC and SC designed the experiments. KVK and SC performed the experiments. VS performed all the sequencing analyses. SM, SB, and GB provided the clinical inputs. KVK, SC and SC wrote the manuscript. SC reviewed and corrected the manuscript and arranged the funds. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Soumen Chakraborty.

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The institutional human ethical committee approved the study (65/HEC/17), and the peripheral blood samples were collected from the patients after obtaining written informed consent. All procedures performed in studies involving human participants were by the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Vinothkumar, K., Chanda, S., Singh, V.K. et al. EVI1 upregulates PTGS1 (COX1) and decreases the action of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia cells. Int J Hematol 117, 110–120 (2023). https://doi.org/10.1007/s12185-022-03465-y

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