Talk abstracts

Talk on Wednesday 04:30-04:45pm submitted by Xiaomeng Huang

Therapeutic Targeting of the RAS-Pathway by Synthetic miR-181a Nanoparticles in Acute Myeloid Leukemia (AML)

Xiaomeng Huang (MCDB), Sebastian Schwind, Ann-Kathrin Eisfeld, Ramasamy Santhanam (Comprehensive Cancer Center), Chi-ling Chiang, Bo Yu (Nanoscale Science and Engineering Center), Rober J Lee (College of Pharmacy), Clara D. Bloomfield, Ramiro Garzon, Guido Marcucci (Comprehensive Cancer Center), L. James Lee (William G. Lowrie Department of Chemical and Biomolecular Engineering)

Abstract:
Deregulated expression of microRNAs has been shown to occur in acute myeloid leukemia (AML) and contribute to the disease aggressiveness. In AML low expression of miR-181a associated with worse outcomes but the exact mechanisms of how miR-181a is mediating this effect remains elusive. Aberrant activation of the RAS-pathway, by mutation or overexpression is also frequent in AML. We hypothesized that miR-181a’s anti-leukemic activity might in part mediate by downregulating the RAS-pathway. Here we showed that the role of miR-181a in modulating the aggressiveness of disease, in vitro and in vivo. Increased miR-181a levels prolonged survival in a murine leukemia model. We showed that miR-181a targets NRAS, KRAS and MAPK1 involved in the oncogenic RAS signaling cascade that support aberrant malignant cell proliferation. To exploit these findings therapeutically we formulated targeted nanoparticles to deliver synthetic miR-181a to AML cells. miR-181a-nanoparticle treatment increased mature miR-181a on average >140-fold and >35-fold in AML cell lines and primary patient blasts, respectively. Delivered miR-181a downregulated KRAS, NRAS and MAPK1 and in turn resulted in decreased phosphorylation of down-stream RAS effectors i.e., AKT and MEK; this in turn results in downregulation of the MAKP1-target oncogenic transcription factor MYC. miR-181a-nanoparticle treatment led to an anti-leukemia activity. It reduced proliferation, impaired colony formation and sensitized AML cells to the chemotherapeutic daunorubicin. Finally, in an AML mouse model miR-181a-nanoparticle treatment resulted in a significantly longer survival. In conclusion, anti-leukemic miR-181a targets the RAS/MAPK-signaling pathway. Treatment with miR-181a-nanoparticles increased miR-181a levels and provides anti-leuemia activity. This may represent a novel therapeutic approach for AML patients.

Keywords: miR-181a, Nanoparticles, Acute Myeloid Leukemia