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

Simple item page
dc.contributor.authorLópez Millán, Belén
dc.contributor.authorAnguita Mandly, Eduardo Luis
dc.contributor.authorMenéndez, Pablo
dc.date.accessioned2024-01-25T13:57:23Z
dc.date.available2024-01-25T13:57:23Z
dc.date.issued2018-07-26
dc.description.abstractTreatment 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 pleio-tropic 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 down-regulation 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.departmentDepto. de Medicina
dc.description.facultyFac. de Medicina
dc.description.refereedTRUE
dc.description.sponsorshipEuropean Research Council
dc.description.sponsorshipMinisterio de Ecolomía y Competitividad
dc.description.sponsorshipGeneralitat de Catalunya
dc.description.sponsorshipISCIII/FEDER
dc.description.sponsorshipAsociación Española Contra el Cancer
dc.description.statuspub
dc.identifier.citationLopez-Millan B, Diaz de la Guardia R, Roca-Ho H, Anguita E, Islam ABMMK, Romero-Moya D, Prieto C, Gutierrez-Agüera F, Bejarano-Garcia JA, Perez-Simon JA, Costales P, Rovira M, Marín P, Menendez S, Iglesias M, Fuster JL, Urbano-Ispizua A, Anjos-Afonso F, Bueno C, Menendez P. 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.
dc.identifier.doi10.1080/2162402x.2018.1477460
dc.identifier.issn2162-402X
dc.identifier.officialurlhttps://www.tandfonline.com/doi/full/10.1080/2162402X.2018.1477460
dc.identifier.urihttps://hdl.handle.net/20.500.14352/95486
dc.issue.number9
dc.journal.titleOncoimmunology
dc.language.isoeng
dc.page.initiale1477460
dc.publisherTaylor and Francis Group
dc.relation.projectIDCoG-2014-646903
dc.relation.projectIDSAF-SAF2013-43065
dc.relation.projectIDRTC-2016-4603-1
dc.relation.projectIDSGR330
dc.relation.projectIDPI14-0119
dc.relation.projectIDAECC-CI-2015
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.cdu616.15
dc.subject.cdu616.155.392
dc.subject.keywordLeucemia mieloide aguda
dc.subject.keywordModelos murinos
dc.subject.keywordTratamiento
dc.subject.ucmHematología
dc.subject.unesco32 Ciencias Médicas
dc.subject.unesco3207.08 Hematología
dc.subject.unesco2407 Biología Celular
dc.titleIMiDs 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.typejournal article
dc.type.hasVersionVoR
dc.volume.number7
dspace.entity.typePublication
relation.isAuthorOfPublicationaa41c8cb-98ce-401a-99fb-32d3a2f96f00
relation.isAuthorOfPublication.latestForDiscoveryaa41c8cb-98ce-401a-99fb-32d3a2f96f00
Download
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC Idarubicin activity in pr.pdf
Size:
3.34 MB
Format:
Adobe Portable Document Format
downoload Download
Collections
Artículos