Jiang, Xi; Bugno, Jason; Hu, Chao; Yang, Yang; Herold, Tobias; Qi, Jun; Chen, Ping; Gurbuxani, Sandeep; Arnovitz, Stephen; Strong, Jennifer; Ferchen, Kyle; Ulrich, Bryan; Weng, Hengyou; Wang, Yungui; Huang, Hao; Li, Shenglai; Neilly, Mary Beth; Larson, Richard A; Le Beau, Michelle M; Bohlander, Stefan K; Jin, Jie; Li, Zejuan; Bradner, James E; Hong, Seungpyo; Chen, Jianjun
Cancer research
2016Aug ; 76 ( 15 ) :4470-80.
PMID : 27280396
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Jiang, Xi -
Bugno, Jason -
Hu, Chao -
Yang, Yang -
Herold, Tobias -
Qi, Jun -
Chen, Ping -
Gurbuxani, Sandeep -
Arnovitz, Stephen -
Strong, Jennifer -
Ferchen, Kyle -
Ulrich, Bryan -
Weng, Hengyou -
Wang, Yungui -
Huang, Hao -
Li, Shenglai -
Neilly, Mary Beth -
Larson, Richard A -
Le Beau, Michelle M -
Bohlander, Stefan K -
Jin, Jie -
Li, Zejuan -
Bradner, James E -
Hong, Seungpyo -
Chen, Jianjun -
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. Cancer Res; 76(15); 4470-80. ??016 AACR. CI - ??016 American Association for Cancer Research.
miR-150, AML, nanoparticles, PAMAM dendrimer, FLT3, FLT3L, MLL-rearranged, MYB, HOXA9, MEIS1, expression, targeted therapy, JQ1
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