Oncotarget

Research Papers:

Targeting the RAS/MAPK pathway with miR-181a in acute myeloid leukemia

Xiaomeng Huang, Sebastian Schwind, Ramasamy Santhanam, Ann-Kathrin Eisfeld, Chi-ling Chiang, Malori Lankenau, Bo Yu, Pia Hoellerbauer, Yan Jin, Somayeh S. Tarighat, Jihane Khalife, Alison Walker, Danilo Perrotti, Clara D. Bloomfield, Hongyan Wang, Robert J. Lee, Ly James Lee and Guido Marcucci _

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Oncotarget. 2016; 7:59273-59286. https://doi.org/10.18632/oncotarget.11150

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Abstract

Xiaomeng Huang1,2,3,*, Sebastian Schwind3,*, Ramasamy Santhanam3, Ann-Kathrin Eisfeld3, Chi-ling Chiang2,3, Malori Lankenau3, Bo Yu2,4, Pia Hoellerbauer3, Yan Jin2, Somayeh S. Tarighat1,3, Jihane Khalife1,3, Alison Walker3, Danilo Perrotti5, Clara D. Bloomfield3, Hongyan Wang3, Robert J. Lee1,2,6, Ly James Lee1,2,4,#, Guido Marcucci1,7,#

1Molecular Cellular and Developmental Biology, The Ohio State University, Columbus, OH, USA

2Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA

3Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

4William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA

5Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA

6Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA

7Gehr Family Leukemia Center, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

*These authors contributed equally to this work

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Correspondence to:

Guido Marcucci, email: gmarcucci@coh.org

Ly James Lee, email: lee.31@osu.edu

Keywords: microRNA, nanoparticles, RAS, miR-181a, acute myeloid leukemia

Received: March 25, 2016     Accepted: July 19, 2016     Published: August 09, 2016

ABSTRACT

Deregulation of microRNAs’ expression frequently occurs in acute myeloid leukemia (AML). Lower miR-181a expression is associated with worse outcomes, but the exact mechanisms by which miR-181a mediates this effect remain elusive. Aberrant activation of the RAS pathway contributes to myeloid leukemogenesis. Here, we report that miR-181a directly binds to 3′-untranslated regions (UTRs); downregulates KRAS, NRAS and MAPK1; and decreases AML growth. The delivery of miR-181a mimics to target AML cells using transferrin-targeting lipopolyplex nanoparticles (NP) increased mature miR-181a; downregulated KRAS, NRAS and MAPK1; and resulted in decreased phosphorylation of the downstream RAS effectors. NP-mediated upregulation of miR-181a led to reduced proliferation, impaired colony formation and increased sensitivity to chemotherapy. Ectopic expression of KRAS, NRAS and MAPK1 attenuated the anti-leukemic activity of miR-181a mimics, thereby validating the relevance of the deregulated miR-181a-RAS network in AML. Finally, treatment with miR-181a-NP in a murine AML model resulted in longer survival compared to mice treated with scramble-NP control. These data support that targeting the RAS-MAPK-pathway by miR-181a mimics represents a novel promising therapeutic approach for AML and possibly for other RAS-driven cancers.


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