RT Journal Article
T1 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
A1 López Millán, Belén
A1 Anguita Mandly, Eduardo Luis
A1 Menéndez, Pablo
AB 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 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.
PB Taylor and Francis Group
SN 2162-402X
YR 2018
FD 2018-07-26
LK https://hdl.handle.net/20.500.14352/95486
UL https://hdl.handle.net/20.500.14352/95486
LA eng
NO Lopez-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.
NO European Research Council
NO Ministerio de Ecolomía y Competitividad
NO Generalitat de Catalunya
NO ISCIII/FEDER
NO Asociación Española Contra el Cancer
DS Docta Complutense
RD 21 ago 2024