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Acute myeloid leukemia

Inhibition of serotonin receptor type 1 in acute myeloid leukemia impairs leukemia stem cell functionality: a promising novel therapeutic target

Leukemia volume 31, pages 2288–2302 (2017)Cite this article

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Abstract

Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous neoplasia with poor outcome, organized as a hierarchy initiated and maintained by a sub-population with differentiation and self-renewal capacities called leukemia stem cells (LSCs). Although currently used chemotherapy is capable of initially reducing the tumor burden producing a complete remission, most patients will ultimately relapse and will succumb to their disease. As such, new therapeutic strategies are needed. AML cells differentially expressed serotonin receptor type 1 (HTR1) compared with healthy blood cells and the most primitive hematopoietic fraction; in fact, HTR1B expression on AML patient samples correlated with clinical outcome. Inhibition of HTR1s activated the apoptosis program, induced differentiation and reduced the clonogenic capacity, while minimal effect was observed on healthy blood cells. In vivo regeneration capacity of primary AML samples was disrupted upon inhibition of HTR1. The self-renewal capacity remaining in AML cells upon in vivo treatment was severely reduced as demonstrated by serial transplantation. Thus, treatment with HTR1 antagonists showed antileukemia effect, especially anti-LSC activity while sparing healthy blood cells. Our results highlight the importance of HTR1 in leukemogenesis and LSC survival and identify this receptor family as a new target for therapy in AML with prognostic value.

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Acknowledgements

We thank Marta Bistagne for her administrative support and all members of the Risueño laboratory for helpful discussions. RMR is supported by Ramón y Cajal program of the Spanish Ministry of Economy (RYC-2011-07998), AE holds a contrato predoctoral para la formación de doctores fellowship (BES-2013-066388), and MN and MAT are supported by Premi Fi de Residència Emili Letang of Hospital Clínic. This work was supported by the Plan Nacional SAF2012-34352 (to RMR), AECC-JP Barcelona (to RMR), the Josep Carreras International Leukaemia Foundation (to RMR), l’Obra Social 'La Caixa'-Fundació Bancària 'La Caixa' (to RMR), RETICC RD12/0036/0010 (to JE and RMR) and FIS PI13/00999 (to JE).

Author contributions

AE, MCL-C, JMC-M, AB-M and MN: acquisition of data, analysis and interpretation of data, and revision of the manuscript; MP, MAT, MD-B and JE: revision of the manuscript and material support; RMR: conception and design, acquisition of data, analysis and interpretation of data and writing the manuscript.

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Authors and Affiliations

  1. Josep Carreras Leukaemia Research Institute, Barcelona, Spain

    A Etxabe, M C Lara-Castillo, J M Cornet-Masana, A Banús-Mulet, M Nomdedeu, M A Torrente, M Pratcorona, J Esteve & R M Risueño

  2. Department of Hematology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    M Nomdedeu, M A Torrente, M Pratcorona, M Díaz-Beyá & J Esteve

  3. University of Barcelona, Barcelona, Spain

    M Díaz-Beyá & J Esteve

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  1. A Etxabe
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Correspondence to R M Risueño.

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The results presented in this paper have been patented. RMR is a shareholder of Leukos Biotech.

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Etxabe, A., Lara-Castillo, M., Cornet-Masana, J. et al. Inhibition of serotonin receptor type 1 in acute myeloid leukemia impairs leukemia stem cell functionality: a promising novel therapeutic target. Leukemia 31, 2288–2302 (2017). https://doi.org/10.1038/leu.2017.52

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