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Comprehensive analysis of cytoskeleton regulatory genes identifies ezrin as a prognostic marker and molecular target in acute myeloid leukemia

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Abstract

Purpose

Despite great advances that have been made in the understanding of the molecular complexity of acute myeloid leukemia (AML), very little has been translated into new therapies. Here, we set out to investigate the impact of cytoskeleton regulatory genes on clinical outcomes and their potential as therapeutic targets in AML.

Methods

Gene expression and clinical data were retrieved from The Cancer Genome Atlas (TCGA) AML study and used for survival and functional genomics analyses. For pharmacological tests, AML cells were exposed to ezrin (EZR) inhibitors and submitted to several cellular and molecular assays.

Results

High EZR expression was identified as an independent marker of worse outcomes in AML patients from the TCGA cohort (p < 0.05). Functional genomics analyses suggested that EZR contributes to responses to stimuli and signal transduction pathways in leukemia cells. EZR pharmacological inhibition with NSC305787 and NSC668394 reduced viability, proliferation, autonomous clonal growth, and cell cycle progression in AML cells (p < 0.05). NSC305787 had a greater potency and efficiency than NSC668394 in leukemia models. At the molecular level, EZR inhibitors reduced EZR, S6 ribosomal protein and 4EBP1 phosphorylation, and induced PARP1 cleavage in AML cells. NSC305787, but not NSC668394, favored a gene network involving cell cycle arrest and apoptosis in Kasumi 1 AML cells.

Conclusions

From our data we conclude that EZR expression may serve as a prognostic factor in AML. Our preclinical findings indicate that ezrin inhibitors may be employed as a putative novel class of AML targeting drugs.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Code availability

Not applicable.

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Acknowledgements

The authors thank Dr. Gabriela Sarti Kinker for providing assistance with the GSEA analysis. The authors also would like to acknowledge all the research participants contributing to The Cancer Genome Atlas (TCGA) resource for providing high quality data for analysis.

Funding

This study was supported by grants #2017/24993-0, #2019/23864-7 and #2015/17177-6 from the São Paulo Research Foundation (FAPESP). This study was also financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.

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Authors and Affiliations

  1. Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, CEP 05508-900, São Paulo, SP, Brazil

    Jean Carlos Lipreri da Silva, Keli Lima, Hugo Passos Vicari, Leticia Veras Costa-Lotufo & João Agostinho Machado-Neto

  2. Department of Medical Imaging, Hematology, and Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil

    Juan Luiz Coelho-Silva & Fabiola Traina

  3. Department of Pharmaceutical Sciences, Federal University of São Paulo, Diadema, Brazil

    Mariana Lazarini

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  1. Jean Carlos Lipreri da Silva
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Contributions

J.C.L.S. conception and design, execution of experiments, data analysis and interpretation, and manuscript writing, J.L.C.-S., H.P.V. and K.L. conception and design, data analysis and interpretation, and manuscript editing. M.L., L.V.C.-L. and F.T. data analysis and interpretation, and manuscript writing. J.A.M.-N. conception and design, data analysis and interpretation, manuscript writing and gave final approval of the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to João Agostinho Machado-Neto.

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Lipreri da Silva, J.C., Coelho-Silva, J.L., Lima, K. et al. Comprehensive analysis of cytoskeleton regulatory genes identifies ezrin as a prognostic marker and molecular target in acute myeloid leukemia. Cell Oncol. 44, 1105–1117 (2021). https://doi.org/10.1007/s13402-021-00621-0

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