Eradication of acute myeloid leukemia with FLT3 ligand-targeted miR-150 nanoparticles

Xi Jiang, Jason Bugno, Chao Hu, Yang Yang, Tobias Herold, Jun Qi, Ping Chen, Sandeep Gurbuxani, Stephen Arnovitz, Jennifer Strong, Kyle Ferchen, Bryan Ulrich, Hengyou Weng, Yungui Wang, Hao Huang, Shenglai Li, Mary Beth Neilly, Richard A. Larson, Michelle M. Le Beau, Stefan K. BohlanderJie Jin, Zejuan Li, James E. Bradner, Seungpyo Hong, Jianjun Chen*

*Corresponding author for this work

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Acute myeloid leukemia (AML) is a common and fatal form of hematopoietic malignancy. Overexpression and/or mutations of FLT3 have been shown to occur in the majority of cases of AML. Our analysis of a large-scale AML patient cohort (N = 562) indicates that FLT3 is particularly highly expressed in some subtypes of AML, such as AML with t(11q23)/MLL-rearrangements or FLT3-ITD. Such AML subtypes are known to be associated with unfavorable prognosis. To treat FLT3-overexpressing AML, we developed a novel targeted nanoparticle system: FLT3 ligand (FLT3L)-conjugated G7 poly(amidoamine) (PAMAM) nanosized dendriplex encapsulating miR-150, a pivotal tumor suppressor and negative regulator of FLT3. We show that the FLT3L-guided miR-150 nanoparticles selectively and efficiently target FLT3-overexpressing AML cells and significantly inhibit viability/growth and promote apoptosis of the AML cells. Our proof-of-concept animal model studies demonstrate that the FLT3L-guided miR-150 nanoparticles tend to concentrate in bone marrow, and significantly inhibit progression of FLT3-overexpressing AML in vivo, while exhibiting no obvious side effects on normal hematopoiesis. Collectively, we have developed a novel targeted therapeutic strategy, using FLT3L-guided miR-150-based nanoparticles, to treat FLT3-overexpressing AML with high efficacy and minimal side effects.

Original languageEnglish (US)
Pages (from-to)4470-4480
Number of pages11
JournalCancer Research
Volume76
Issue number15
DOIs
StatePublished - Aug 1 2016

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Jiang, X., Bugno, J., Hu, C., Yang, Y., Herold, T., Qi, J., Chen, P., Gurbuxani, S., Arnovitz, S., Strong, J., Ferchen, K., Ulrich, B., Weng, H., Wang, Y., Huang, H., Li, S., Neilly, M. B., Larson, R. A., Le Beau, M. M., ... Chen, J. (2016). Eradication of acute myeloid leukemia with FLT3 ligand-targeted miR-150 nanoparticles. Cancer Research, 76(15), 4470-4480. https://doi.org/10.1158/0008-5472.CAN-15-2949