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 Lopez-Millan, Belen
A1 Diaz de la Guardia, Rafael
A1 Roca-Ho, Heleia
A1 Anguita, Eduardo
A1 Islam, Abul B M M K
A1 Romero-Moya, Damia
A1 Prieto, Cristina
A1 Gutierrez-Agüera, Francisco
A1 Bejarano-Garcia, Jose Antonio
A1 Perez-Simon, Jose Antonio
A1 Costales, Paula
A1 Rovira, Montse
A1 Marín, Pedro
A1 Menendez, Silvia
A1 Iglesias, Mar
A1 Fuster, Jose Luis
A1 Urbano-Ispizua, Alvaro
A1 Anjos-Afonso, Fernando
A1 Bueno, Clara
A1 Menendez, Pablo
K1 AML
K1 AraC
K1 BM-MSC
K1 IMiDs
K1 Idarubicin
K1 lenalidomide
K1 pomalidomide
K1 xenografts
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 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.
SN 2162-4011
YR 2018
FD 2018-07-26
LK http://hdl.handle.net/10668/12963
UL http://hdl.handle.net/10668/12963
LA en
DS RISalud
RD Apr 5, 2025