TY - JOUR
T1 - Eradication of acute myeloid leukemia with FLT3 ligand-targeted miR-150 nanoparticles
AU - Jiang, Xi
AU - Bugno, Jason
AU - Hu, Chao
AU - Yang, Yang
AU - Herold, Tobias
AU - Qi, Jun
AU - Chen, Ping
AU - Gurbuxani, Sandeep
AU - Arnovitz, Stephen
AU - Strong, Jennifer
AU - Ferchen, Kyle
AU - Ulrich, Bryan
AU - Weng, Hengyou
AU - Wang, Yungui
AU - Huang, Hao
AU - Li, Shenglai
AU - Neilly, Mary Beth
AU - Larson, Richard A.
AU - Le Beau, Michelle M.
AU - Bohlander, Stefan K.
AU - Jin, Jie
AU - Li, Zejuan
AU - Bradner, James E.
AU - Hong, Seungpyo
AU - Chen, Jianjun
N1 - Funding Information:
J.E. Bradner is the President at Novartis Institute of BioMedical Research. No potential conflicts of interest were disclosed by the other authors. Special thanks to our late mentor and colleague Dr. Janet Rowley for her long-term support. The authors thank Drs. Scott Armstrong, Gregory Hannon, and Lin He for providing retroviral constructs. The authors also thank all participants and recruiting centers of the Acute Myeloid Leukemia Cooperative Group (AMLCG) trials. This work was supported by the NIH R01 grants CA182528, CA178454, and CA127277 (J. Chen), Alex's Lemonade Stand Foundation for Childhood Cancer (J. Chen); Leukemia and Lymphoma Society (LLS) Translational Research Grant (J. Chen), American Cancer Society (ACS) Research Scholar grant (J. Chen), The University of Chicago Committee on Cancer Biology (CCB) Fellowship Program (X. Jiang), LLS Special Fellowship (Z. Li), Gabrielle's Angel Foundation for Cancer Research (J. Chen, Z. Li, X. Jiang, and H. Huang), and the family of Marijanna Kumerich and Leukemia and Blood Cancer New Zealand (S.K. Bohlander). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 AACR.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84982671713&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-15-2949
DO - 10.1158/0008-5472.CAN-15-2949
M3 - Article
C2 - 27280396
AN - SCOPUS:84982671713
VL - 76
SP - 4470
EP - 4480
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 15
ER -
