IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q-AML

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• dc.contributor.author López Millán, Belén
• dc.contributor.author Menéndez, Silvia
• dc.contributor.author Iglesias Coma, Mar
• dc.contributor.author Menéndez, Pablo
• dc.date.accessioned 2019-06-27T07:33:46Z
• dc.date.available 2019-06-27T07:33:46Z
• dc.date.issued 2018
• dc.description.abstract Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk between AML cells and the BM stroma is a major mechanism underlying therapy resistance in AML. Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma. Whether IMiDs may improve the efficacy of current standard treatment in AML remains understudied. Here, we have exploited in vitro and in vivo preclinical AML models to analyze whether IMiDs potentiate the efficacy of AraC/Idarubicin-based standard AML chemotherapy by interfering with the BM stroma-mediated chemoresistance. We report that IMiDs do not exert cytotoxic effects on either non-del5q/5q- AML cells nor BM-MSCs, but they enhance the immunomodulatory properties of BM-MSCs. When combined with AraC/Idarubicin, IMiDs fail to circumvent BM stroma-mediated resistance of non-del5q/5q- AML cells in vitro and in vivo but induce robust extramedullary mobilization of AML cells. When administered as a single agent, lenalidomide specifically mobilizes non-del5q/5q- AML cells, but not healthy CD34+ cells, to peripheral blood (PB) through specific downregulation of CXCR4 in AML blasts. Global gene expression profiling supports a migratory/mobilization gene signature in lenalidomide-treated non-del5q/5q- AML blasts but not in CD34+ cells. Collectively, IMiDs mobilize non-del5q/5q- AML blasts to PB through CXCR4 downregulation, but fail to potentiate AraC/Idarubicin activity in preclinical models of non-del5q/5q- AML.
• dc.description.sponsorship This work was supported by the European Research Council (CoG-2014-646903 to P.M), the Spanish Ministry of Economy and Competitiveness (SAF-SAF2013-43065, RTC-2016-4603-1 to P.M), the Asociación Española Contra el Cáncer (AECC-CI-2015), FERO Foundation, and the ISCIII/FEDER (PI14-01191) to C.B and the ‘‘Fundación Hay Esperanza’’ to E.A. P.M also acknowledges financial support from The Obra Social La Caixa-Fundaciò Josep Carreras, The Inocente Inocente Foundation and The Generalitat de Catalunya (SGR330). P.M an investigator of the Spanish Cell Therapy cooperative network (TERCEL). We thank Celgene Corporation (San Diego, CA) for providing IMiDs. We thank Judit Sopena and Mariano Graupera (IDIBELL, Barcelona) for their technical assistance with immunohistochamical analysis
• dc.format.mimetype application/pdf
• dc.identifier.citation Lopez-Millan B, Diaz de la Guardia R, Roca-Ho H, Anguita E, Islam ABMMK, Romero-Moya D. et al. IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML. Oncoimmunology. 2018 Jul 26;7(9):e1477460. DOI: 10.1080/2162402X.2018.1477460
• dc.identifier.doi http://dx.doi.org/10.1080/2162402X.2018.1477460
• dc.identifier.issn 2162-4011
• dc.identifier.uri http://hdl.handle.net/10230/41876
• dc.language.iso eng
• dc.publisher Taylor & Francis
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-43065
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/RTC2016-4603-1
• dc.rights Copyright © 2018 Taylor & Francis Group, LLC. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword AML
• dc.subject.keyword AraC
• dc.subject.keyword BM-MSC
• dc.subject.keyword IMiDs
• dc.subject.keyword Idarubicin
• dc.subject.keyword Lenalidomide
• dc.subject.keyword Pomalidomide
• dc.subject.keyword Xenografts
• dc.title IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q-AML
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion