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Myeloid Cell-Targeted miR-146a Mimic Inhibits NF-kB-Driven Inflammation and Leukemia Progression in Vivo

Su, Yu-Lin and Wang, Xiuli and Mann, Mati and Adamus, Tomasz and Wang, Dongfang and Moreira, Dayson and Zhang, Zhuoran and Ouyang, Ching and He, Xin and Zhang, Bin and Swiderski, Piotr and Forman, Stephen and Baltimore, David and Li, Ling and Marcucci, Guido and Boldin, Mark P. and Kortylewski, Marcin (2020) Myeloid Cell-Targeted miR-146a Mimic Inhibits NF-kB-Driven Inflammation and Leukemia Progression in Vivo. Blood, 135 (3). pp. 167-180. ISSN 0006-4971. PMCID PMC6966933 . https://resolver.caltech.edu/CaltechAUTHORS:20191218-082734179

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Abstract

NF-κB is a key regulator of inflammation and cancer progression, with an important role in leukemogenesis. Despite its therapeutic potential, targeting NF-κB using pharmacologic inhibitors has proven challenging. Here, we describe a myeloid cell–selective NF-κB inhibitor using an miR-146a mimic oligonucleotide conjugated to a scavenger receptor/Toll-like receptor 9 agonist (C-miR146a). Unlike an unconjugated miR146a, C-miR146a was rapidly internalized and delivered to the cytoplasm of target myeloid cells and leukemic cells. C-miR146a reduced expression of classic miR-146a targets (IRAK1 and TRAF6), thereby blocking activation of NF-κB in target cells. IV injections of C-miR146a mimic to miR-146a–deficient mice prevented excessive NF-κB activation in myeloid cells, and thus alleviated myeloproliferation and mice hypersensitivity to bacterial challenge. Importantly, C-miR146a showed efficacy in dampening severe inflammation in clinically relevant models of chimeric antigen receptor (CAR) T-cell–induced cytokine release syndrome. Systemic administration of C-miR146a oligonucleotide alleviated human monocyte-dependent release of IL-1 and IL-6 in a xenotransplanted B-cell lymphoma model without affecting CD19-specific CAR T-cell antitumor activity. Beyond anti-inflammatory functions, miR-146a is a known tumor suppressor commonly deleted or expressed at reduced levels in human myeloid leukemia. Using The Cancer Genome Atlas acute myeloid leukemia data set, we found an inverse correlation of miR-146a levels with NF-κB–related genes and with patient survival. Correspondingly, C-miR146a induced cytotoxic effects in human MDSL, HL-60, and MV4-11 leukemia cells in vitro. The repeated IV administration of C-miR146a inhibited expression of NF-κB target genes and thereby thwarted progression of disseminated HL-60 leukemia. Our results show the potential of using myeloid cell–targeted miR-146a mimics for the treatment of inflammatory and myeloproliferative disorders.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1182/blood.2019002045DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6966933/PubMed CentralArticle
ORCID:
AuthorORCID
Zhang, Bin0000-0002-3685-7503
Baltimore, David0000-0001-8723-8190
Boldin, Mark P.0000-0003-4593-0669
Alternate Title:Myeloid cell-targeted miR146a for NF-κB inhibition
Additional Information:© 2020 American Society of Hematology. Submitted 17 June 2019; accepted 1 November 2019; prepublished online on Blood First Edition 5 December 2019. DOI 10.1182/blood.2019002045. The authors thank and acknowledge the dedication of staff members at the DNA/RNA Synthesis, Analytical Cytometry, Light Microscopy Cores and Animal Resources Center (City of Hope). This work was supported in part by the National Cancer Institute/National Institutes of Health awards R01CA213131 (M.K.), Lymphoma Specialized Program of Research Excellence P50CA107399 (S.J.F.), and P30CA033572 (to the City of Hope). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Authorship: Contribution: Y.-L.S. and M.K. were responsible for study design; Y.-L.S., X.W., M.M., T.P.A., D.F.M., Z.Z., D.W., P.M.S., and M.K. performed data acquisition; Y.-L.S., M.M., T.P.A., D.F.M., D.W., and C.O. analyzed and interpreted the data; Y.-L.S., X.W., X.H., B.Z., P.M.S., S.J.F., D.B., L.L., G.M., M.P.B., and M.K. were responsible for administrative, technical, or material support; and Y.-L.S. and M.K. wrote the manuscript. Conflict-of-interest disclosure: M.K., P.M.S., and G.M. have a patent on C-miRNA conjugates and uses thereof compositions for the treatment of cancers and other diseases. The remaining authors declare no competing financial interests. The data reported in this article have been deposited in the Gene Expression Omnibus database (accession number GSE141402). The online version of this article contains a data supplement. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
Funders:
Funding AgencyGrant Number
NIHR01CA213131
NIHP50CA107399
NIHP30CA033572
Subject Keywords:cd19 antigens, inflammation, leukemia, leukemia, myeloid, lymphoma, oligonucleotides, toll-like receptor 9, agonists, anti-inflammatory agents, chimeric antigen receptors
Issue or Number:3
PubMed Central ID:PMC6966933
Record Number:CaltechAUTHORS:20191218-082734179
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20191218-082734179
Official Citation:Yu-Lin Su, Xiuli Wang, Mati Mann, Tomasz P. Adamus, Dongfang Wang, Dayson F. Moreira, Zhuoran Zhang, Ching Ouyang, Xin He, Bin Zhang, Piotr M. Swiderski, Stephen J. Forman, David Baltimore, Ling Li, Guido Marcucci, Mark P. Boldin, Marcin Kortylewski; Myeloid cell–targeted miR-146a mimic inhibits NF-κB–driven inflammation and leukemia progression in vivo. Blood 2020; 135 (3): 167–180. doi: https://doi.org/10.1182/blood.2019002045
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100339
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:18 Dec 2019 19:47
Last Modified:02 Apr 2020 21:07

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