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ABSTRACT CD69 regulates lymphocyte egress from the thymus and lymph nodes through cis-interactions and the downregulation of surface sphingosine-1-phosphate (S1P) receptor-1 (S1P1). However,

its role in the regulation of cell egress from bone marrow has not been extensively studied. We show here that CD69 targeting induced rapid and massive mobilization of BM leukocytes, which

was inhibited by desensitization to S1P with FTY720. This mobilization was reproduced with anti-human CD69 mAb treatment of mice expressing human CD69. In this strain, the mobilization

occurred to the same extent as that induced by AMD3100. The anti-human CD69 treatment highly increased LSK and CLP cell proliferation and numbers, both in the periphery and in the BM, and

also augmented S1P1 and CXCR4 expression. Additionally, increased mTOR, p70S6K, S6, and 4E-BP1 phosphorylation was detected after in vivo anti-CD69 treatment in the bone marrow. Importantly,

mTOR inhibition with rapamycin inhibited anti-huCD69-induced mobilization of hematopoietic stem and progenitor cells (HSPCs). Together, our results indicated that CD69 targeting induces not

only mobilization but also high proliferation of HSPCs, and thus is crucial for precursor cell replenishment over time. These results suggest that anti-CD69 mAbs are putative novel

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  PubMed Central  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS The study was supported by the Instituto de Salud Carlos III MPY 1366/13 and MPY 1346/16. ML was supported by

SAF2015-74112-JIN from MINECO. GS was supported by ERC 260464, EFSD 2030, MINECO-FEDER SAF2016-79126-R, and Comunidad de Madrid S2010/BMD-2326. The CNIC is supported by the Ministerio de

Economía y Competitividad and the Pro-CNIC Foundation. The Pro-CNIC Foundation is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). We are grateful to Dra Ana Justel, of UAM,

for help in statistical analysis. We thank Daniel Baizan, Cristina Pintos, and Maria Clemente for mouse husbandry. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Microbiology National

Center, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain Laura Notario, Almudena Albentosa & Pilar Lauzurica * Universitat Pompeu Fabra, Barcelona, Spain Elisenda Alari-Pahissa

* Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain Magdalena Leiva & Guadalupe Sabio Authors * Laura Notario View author publications You can also

search for this author inPubMed Google Scholar * Elisenda Alari-Pahissa View author publications You can also search for this author inPubMed Google Scholar * Almudena Albentosa View author

publications You can also search for this author inPubMed Google Scholar * Magdalena Leiva View author publications You can also search for this author inPubMed Google Scholar * Guadalupe

Sabio View author publications You can also search for this author inPubMed Google Scholar * Pilar Lauzurica View author publications You can also search for this author inPubMed Google

Scholar CORRESPONDING AUTHOR Correspondence to Pilar Lauzurica. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare that they have no conflict of interest. ELECTRONIC SUPPLEMENTARY

MATERIAL SUPPLEMENTARY DATA RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Notario, L., Alari-Pahissa, E., Albentosa, A. _et al._ Anti-CD69 therapy

induces rapid mobilization and high proliferation of HSPCs through S1P and mTOR. _Leukemia_ 32, 1445–1457 (2018). https://doi.org/10.1038/s41375-018-0052-x Download citation * Received: 23

August 2017 * Revised: 30 December 2017 * Accepted: 11 January 2018 * Published: 27 February 2018 * Issue Date: June 2018 * DOI: https://doi.org/10.1038/s41375-018-0052-x SHARE THIS ARTICLE

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