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 miR181a 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.

Up-Regulation of the miR-92a and miR-181a in Patients with Acute Myeloid Leukemia and their Inhibition with Locked Nucleic acid (LNA)-antimiRNA; Introducing c-Kit as a New Target Gene

“…28 Consistent with these results, Nanbakhsh et al also showed that overexpression of miR-181a in AML blasts is associated with attenuation of their resistance to daunorubicin (DNR) and NK-cell-mediated killing, supporting that high miR-181a might be implicated in the chemosensitization of leukemic cells to DNR and NK cells-mediated lysis. 21 Unexpectedly, we observed that miR-181a but not miR-92a is upregualted in high risk AML patients. However, in a meta-analysis by Guo et al, it was showed that elevated miR-181 expression was associated with increased survival in American AML patients, while with reduced survival in Chinese patients, indicating that miR-181 can be used as a prognostic biomarker in AML patients depending on the origin of patient population.…”

“…There are various reports describing that miR-92a and miR-181a are involved in cell cycle regulation and cell signaling by targeting genes promoting cell differentiation, apoptosis and those inhibiting cell proliferation. [19][20][21] In two separate study by Sharifi et al, inhibition of miR-92a with LNA-anti-miR-92a, reduced survival and induced cell apoptosis and necrosis in human acute megakaryoblastic (M-07e) and acute promyelocytic leukemia (HL-60) cell line. 22,23 Liu et al explained that transfection of HL-60 cell line with miR-181a mimic significantly increased G1/S cell cycle transition and cell proliferation suggesting that miR-181a may contribute to AML progression by promoting myeloid cell proliferation.…”

Mir-181c Modulates T Cell Function By Regulating the Expression of BRK1

“…This finding is consistent with Nanbakhsh et al study where they found that downregulation of miR-181a was associated with the acquisition of resistance to daunorubicin and cross-resistance of NK cell-mediated cytotoxicity in AML cell lines (U937 and KG1) through regulation of the tyrosine kinases, MAP3K10 and MAP2K1, and the BCL2 (BCL2 and MCL1) family. Reduced expression of miR-181a was also observed in refractory primary AML blasts and overexpression of miR-181a in AML blasts attenuated their resistance to daunorubicin and to NK cell-mediated killing (Nanbakhsh et al, 2015). In a more recent study, downregulation of miR-181 was seen in older AML patients treated with the hypomethylating drug azacitidine and the lower miR-181 expression was shown as an independent predictor for good response to treatment and prolonged survival in this patient group (Butrym et al, 2016).…”

An overview of the potential strategies for NK cell‐based immunotherapy for acute myeloid leukemia

“…In addition to their direct cytotoxicity, the synergistic effect between these drugs and NK cells holds great promise for AML therapy. Daunorubicin‐resistant leukemia blasts are also resistant to NK‐mediated cytolysis because of the downregulation of miR‐181a . Therefore, upregulating miR‐181a expression may be an option for NK‐based immunotherapy of chemotherapy‐resistant AML.…”