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 language | English (US) |
|---|---|
| Pages (from-to) | 4470-4480 |
| Number of pages | 11 |
| Journal | Cancer Research |
| Volume | 76 |
| Issue number | 15 |
| DOIs | |
| State | Published - Aug 1 2016 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
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Eradication of acute myeloid leukemia with FLT3 ligand-targeted miR-150 nanoparticles. / 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.
In: Cancer Research, Vol. 76, No. 15, 01.08.2016, p. 4470-4480.Research output: Contribution to journal › Article
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
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.
UR - http://www.scopus.com/inward/record.url?scp=84982671713&partnerID=8YFLogxK
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 - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 15
ER -