title: miR-181a modulates acute myeloid leukemia susceptibility to natural killer cells.
abstract: Although daunorubicin (DNR) is the most widely used anthracycline to treat acute myeloid leukemia (AML), resistance to this drug remains a critical problem. The aim of this study was to investigate the relationship between AML resistance to daunorubicin and susceptibility to natural killer (NK) cell-mediated cell lysis, and the putative expression of miRs. For this purpose, we used the parental AML cell lines U-937 and KG-1 and their equivalent resistant U937(R) and KG-1(R) cell lines. We demonstrate for the first time that the acquisition of resistance to DNR by the parental cell lines resulted in the acquisition of cross-resistance to NK cell-mediated cytotoxicity. miR microarray analysis revealed that this cross-resistance was associated with miR-181a downregulation and the subsequent regulation of MAP3K10 and MAP2K1 tyrosine kinases and the BCL-2 (BCL-2 and MCL-1) family. Overexpression of miR-181a in AML blasts resulted in the attenuation of their resistance to DNR and to NK-cell-mediated killing. These data point to a determinant role of miR-181a in the sensitization of leukemic resistant cells to DNR and NK cells and suggest that miR-181a may provide a promising option for the treatment of immuno- and chemo-resistant blasts.
authors.affiliation: INSERM; Gustave Roussy Campus ; Villejuif, France.
authors.forename: Arash
authors.initials: A
authors.lastname: Nanbakhsh
authors.affiliation: INSERM; Gustave Roussy Campus ; Villejuif, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Visentin
authors.affiliation: Centre de Cancérologie de Marseille; INSERM; Institut Paoli-Calmettes ; Marseille, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Olive
authors.affiliation: Laboratory of Experimental Hemato-Oncology. CRP-Santé ,; Luxembourg City, Luxembourg.
authors.forename: Bassam
authors.initials: B
authors.lastname: Janji
authors.affiliation: CNRS-UMR 8126; Gustave Roussy Campus ; Villejuif, France.
authors.forename: Eugenie
authors.initials: E
authors.lastname: Mussard
authors.affiliation: Functional Genomic Unit; Gustave Roussy Campus ; Villejuif, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Dessen
authors.affiliation: Functional Genomic Unit; Gustave Roussy Campus ; Villejuif, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Meurice
authors.affiliation: INSERM; Gustave Roussy Campus ; Villejuif, France.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: INSERM; Gustave Roussy Campus ; Villejuif, France.
authors.forename: Fawzia
authors.initials: F
authors.lastname: Louache
authors.affiliation: INSERM; Gustave Roussy Campus ; Villejuif, France ; Department of Hematology & Bone Marrow Transplantation, Gustave Roussy Campus ; Villejuif, France.
authors.forename: Jean-Henri
authors.initials: JH
authors.lastname: Bourhis
authors.affiliation: INSERM; Gustave Roussy Campus ; Villejuif, France.
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
keywords: AML; NK lysis; miR-181a