miR-181b increases drug sensitivity in acute myeloid leukemia via targeting HMGB1 and Mcl-1

Abstract

Abstract. Multidrug resistance (MDR) remains the major cause of disease relapse and poor prognosis in adults with acute myeloid leukemia (AML). Emerging evidence shows that drug resistance not only exists against conventional chemotherapeutic drugs, but also limits the efficacy of new biological agents. Therefore, it is important to elucidate the mechanisms through which AML patients develop drug resistance. MicroRNAs have been shown to play an important role in regulating the chemotherapy resistance in AML. A detailed understanding of the mechanisms of microRNA that are clinically relevant in AML may enhance our ability to predict and overcome drug resistance. Here, we demonstrated, for the first time, that miR-181b was decreased significantly in human multidrug-resistant leukemia cells and relapsed/refractory AML patient samples. Overexpression of miR-181b increased the sensitivity of leukemia cells to cytotoxic chemotherapeutic agents and promoted drug-induced apoptosis. Moreover, miR-181b inhibited HMGB1 and Mcl-1 expression by direct binding to their 3'-untranslated regions. In addition, HMGB1 was expressed at high levels in relapsed/refractory AML patients and suppression of HMGB1 via RNA interference sensitized multidrug-resistant leukemia cells to chemotherapy and induced apoptosis. In conclusion, these results provide a strong rationale for the development of miR-181b-based therapeutic strategies for the enhancement of efficacy in AML treatment.

Alpha-2, 3-sialyltransferases regulate the multidrug resistance of chronic myeloid leukemia through miR-4701-5p targeting ST3GAL1

“…16,17 MiR-181b was decreased significantly in human multidrug-resistant leukemia cells and increased the sensitivity of leukemia cells to cytotoxic chemotherapeutic agents. 18 MiR-381 and miR-495 modulated the MDR phenotype of leukemia K562/ ADM cells and were associated inversely with the expression of the MDR1 gene and its protein product, P-glycoprotein. 19 Altered expression of miR-331-5p and miR-27a were correlated with leukemia cell resistance and relapse.…”

miR-181a modulates acute myeloid leukemia susceptibility to natural killer cells

“…Recently, in a similar study, it has been demonstrated miR181b (another family of this microRNA) increases drug sensitivity in AML by targeting HMGB1 and MCL -1. 51 In this report, the authors found modification of these genes in all three tested patients. AML comprises a heterogeneous group of malignancies with diverse origins.…”

“…The cytotoxic activity of the NK cells was measured by a conventional 4-h 51 Cr release assay by using triplicate cultures in round-bottom 96-well plates. Different E: T ratios were used as described earlier.…”

Small Non-Coding RNAs in Regulation of Course and Therapeutic Efficacy in Acute Myeloid Leukemia

“…Group 1 characterized with high level of expression of sncRNAs, which associated with sensitivity to therapy. This group members are miRNA-181a, b; let-7f, miRNA-9*, miRNA-96, miRNA-135a, miRNA-409, miRNA-10, miRNA29b and miRNA-217 [72,73,[97][98][99][100]. Group 1 members act through activation of cellular differentiation, inhibition of leukemic cells proliferation and survival, regulation of cell cycle, inducing of apoptosis and suppression of migration and invasion.…”