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

18 Citations (Scopus)

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

Fingerprint

Acute Myeloid Leukemia
Nanoparticles
Ligands
Myeloid Cells
Hematopoiesis
Hematologic Neoplasms
Animal Models
Bone Marrow
Apoptosis
Mutation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. / Eradication of acute myeloid leukemia with FLT3 ligand-targeted miR-150 nanoparticles. In: Cancer Research. 2016 ; Vol. 76, No. 15. pp. 4470-4480.
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title = "Eradication of acute myeloid leukemia with FLT3 ligand-targeted miR-150 nanoparticles",
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.",
author = "Xi Jiang and Jason Bugno and Chao Hu and Yang Yang and Tobias Herold and Jun Qi and Ping Chen and Sandeep Gurbuxani and Stephen Arnovitz and Jennifer Strong and Kyle Ferchen and Bryan Ulrich and Hengyou Weng and Yungui Wang and Hao Huang and Shenglai Li and Neilly, {Mary Beth} and Larson, {Richard A.} and {Le Beau}, {Michelle M.} and Bohlander, {Stefan K.} and Jie Jin and Zejuan Li and Bradner, {James E.} and Seungpyo Hong and Jianjun Chen",
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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, MB, Larson, RA, Le Beau, MM, Bohlander, SK, Jin, J, Li, Z, Bradner, JE, Hong, S & Chen, J 2016, 'Eradication of acute myeloid leukemia with FLT3 ligand-targeted miR-150 nanoparticles', Cancer Research, vol. 76, no. 15, pp. 4470-4480. https://doi.org/10.1158/0008-5472.CAN-15-2949

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 journalArticle

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.

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