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STMN1 is highly expressed and contributes to clonogenicity in acute promyelocytic leukemia cells

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Summary

Stathmin 1 (STMN1) is a microtubule-destabilizing protein highly expressed in hematological malignancies and involved in proliferation and differentiation. Although a previous study found that the PML–RARα fusion protein, which contributes to the pathophysiology of acute promyelocytic leukemia (APL), positively regulates STMN1 at the transcription and protein activity levels, little is known about the role of STMN1 in APL. In this study, we aimed to investigate the STMN1 expression levels and their associations with laboratory, clinical, and genomic data in APL patients. We also assessed the dynamics of STMN1 expression during myeloid cell differentiation and cell cycle progression, and the cellular effects of STMN1 silencing and pharmacological effects of microtubule-stabilizing drugs on APL cells. We found that STMN1 transcripts were significantly increased in samples from APL patients compared with those of healthy donors (all p < 0.05). However, this had no effect on clinical outcomes. STMN1 expression was associated with proliferation- and metabolism-related gene signatures in APL. Our data confirmed that STMN1 was highly expressed in early hematopoietic progenitors and reduced during cell differentiation, including the ATRA-induced granulocytic differentiation model. STMN1 phosphorylation was predominant in a pool of mitosis-enriched APL cells. In NB4 and NB4-R2 cells, STMN1 knockdown decreased autonomous cell growth (all p < 0.05) but did not impact ATRA-induced apoptosis and differentiation. Finally, treatment with paclitaxel (as a single agent or combined with ATRA) induced microtubule stabilization, resulting in mitotic catastrophe with repercussions for cell viability, even in ATRA-resistant APL cells. This study provides new insights into the STMN1 functions and microtubule dynamics in APL.

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Data availability

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

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Acknowledgements

The authors thank John De Vos and Tanguy Le Carrour for led the initiative Amazonia! (http://amazonia.transcriptome.eu), providing a tool for analysis of genomic data. The authors also thank Professor Francisco Garcia Soriano (Internal Medicine Department, School of Medicine, University of São Paulo) for kindly providing the olaparib used in this study.

Funding

This study was supported by grant #2019/23864–7, #2017/24993–0, #2017/23117–1, #2020/12842–0 and #2019/01700–2 from the São Paulo Research Foundation (FAPESP), and grant #402587/2016–2 form the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001.

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Author notes

  1. Hugo Passos Vicari and Juan Luiz Coelho-Silva Contributed equally to the study.

Authors and Affiliations

  1. Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil

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

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

    Juan Luiz Coelho-Silva, Diego A. Pereira-Martins, Priscila Santos Scheucher, Luisa C. Koury, Lorena Lobo de Figueiredo-Pontes & Fabiola Traina

  3. Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in Onco-Immuno-Hematology (LIM-31), Department of Hematology, Faculdade de Medicina, Hospital das Clínicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil

    Diego A. Pereira-Martins, Keli Lima & Eduardo Magalhães Rego

  4. Department of Genetics, Federal University of Pernambuco, Recife, Brazil

    Antônio Roberto Lucena-Araujo

  5. Department of Internal Medicine, University of Pernambuco and Fundação HEMOPE, Recife, Brazil

    Raul A. de Melo

  6. Hematology Division, University Hospital of the Federal University of Rio Grande Do Sul, Porto Alegre, Brazil

    Rosane Bittencourt

  7. University of Campinas/Hemocentro-Unicamp, Campinas, Brazil

    Katia Pagnano

  8. Hematology Division, Federal University of Paraná, Curitiba, Brazil

    Elenaide Nunes

  9. Hematology Division, Federal University of Minas Gerais, Belo Horizonte, Brazil

    Evandro M. Fagundes

  10. Hematology Division, Federal University of Sao Paulo, Sao Paulo, Brazil

    Fabio Kerbauy

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  1. Hugo Passos Vicari
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Contributions

H.P.V and J.L.C.-S. designed, executed and analyzed the experiments and prepared the manuscript. D.A.P.-M., A.R.L.-A, K.L., J.C.L.S., and L.V.C.-L. provided inputs and participated in experiments. P.S.S. participated in flow cytrometry experiments and data analysis. L.C.K., R.A.M., R.B.B., K.P., E.N., E.M.F., F.K., L.L.F.-P., and E.M.R contributed recruiting patients and collecting data. F.T. and J.A.M.-N. supervised and participated in overall design of study, experiments and analyses, and prepared the manuscript. All authors reviewed and edited the manuscript.

Corresponding authors

Correspondence to Fabiola Traina or João Agostinho Machado-Neto.

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Ethical approval

All procedures used were approved by the Ethics Committee of the Medical School of Ribeirao Preto, University of Sao Paulo, and by the National Commission of Ethics in Research, National Health Council, Ministry of Health (CONEP) (Registry# 12920; Process number: 13496/2005; CAAE: 155.0.004.000–05). Informed consent was obtained from all patients and approved by the Research Ethics Board. All methods were carried out in accordance with the approved guidelines and to the Declaration of Helsinki.

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Conflict of interest

Hugo Passos Vicari declares that he has no conflict of interest. Juan Luiz Coelho-Silva declares that he has no conflict of interest. Diego A. Pereira-Martins declares that he has no conflict of interest. Antônio Roberto Lucena-Araujo declares that he has no conflict of interest. Keli Lima declares that she has no conflict of interest. Jean Carlos Lipreri da Silva declares that he has no conflict of interest. Priscila Santos Scheucher declares that she has no conflict of interest. Luisa C. Koury declares that she has no conflict of interest. Raul A. de Melo declares that he has no conflict of interest. Rosane Bittencourt declares that she has no conflict of interest. Katia Pagnano declares that she has no conflict of interest. Elenaide Nunes declares that she has no conflict of interest. Evandro M. Fagundes declares that he has no conflict of interest. Fabio Kerbauy declares that he has no conflict of interest. Lorena Lobo de Figueiredo-Pontes declares that she has no conflict of interest. Leticia Veras Costa-Lotufo declares that she has no conflict of interest. Eduardo Magalhães Rego declares that he has no conflict of interest. Fabiola Traina declares that she has no conflict of interest. João Agostinho Machado-Neto declares that he has no conflict of interest.

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Vicari, H.P., Coelho-Silva, J.L., Pereira-Martins, D.A. et al. STMN1 is highly expressed and contributes to clonogenicity in acute promyelocytic leukemia cells. Invest New Drugs 40, 438–452 (2022). https://doi.org/10.1007/s10637-021-01197-0

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