دورية أكاديمية
أعرض في EDS

Myeloid cell-targeted miR-146a mimic inhibits NF-κB-driven inflammation and leukemia progression in vivo.

التفاصيل البيبلوغرافية
العنوان: Myeloid cell-targeted miR-146a mimic inhibits NF-κB-driven inflammation and leukemia progression in vivo.
المؤلفون: Su YL; Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA., Wang X; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, CA., Mann M; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA., Adamus TP; Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA., Wang D; Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA., Moreira DF; Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA., Zhang Z; Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA., Ouyang C; Center for Informatics, City of Hope National Medical Center, Duarte, CA.; Department of Computational and Quantitative Medicine, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA., He X; Department of Hematologic Malignancies Translational Science, Gehr Family Leukemia Center at City of Hope Comprehensive Cancer Center, Duarte, CA; and., Zhang B; Department of Hematologic Malignancies Translational Science, Gehr Family Leukemia Center at City of Hope Comprehensive Cancer Center, Duarte, CA; and., Swiderski PM; DNA/RNA Synthesis Core Laboratory., Forman SJ; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, CA., Baltimore D; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA., Li L; Department of Hematologic Malignancies Translational Science, Gehr Family Leukemia Center at City of Hope Comprehensive Cancer Center, Duarte, CA; and., Marcucci G; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, CA.; Department of Hematologic Malignancies Translational Science, Gehr Family Leukemia Center at City of Hope Comprehensive Cancer Center, Duarte, CA; and., Boldin MP; Department of Molecular and Cellular Biology, and., Kortylewski M; Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA.; Center for Gene Therapy, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA.
المصدر: Blood [Blood] 2020 Jan 16; Vol. 135 (3), pp. 167-180.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE
أسماء مطبوعة: Publication: 2021- : [New York] : Elsevier
Original Publication: New York, Grune & Stratton [etc.]
مواضيع طبية MeSH: Cytokine Release Syndrome/*prevention & control , Inflammation/*prevention & control , Leukemia, Myeloid, Acute/*prevention & control , MicroRNAs/*genetics , Myeloid Progenitor Cells/*pathology , NF-kappa B/*metabolism, Animals ; Apoptosis ; Cell Proliferation ; Cytokine Release Syndrome/genetics ; Cytokine Release Syndrome/pathology ; Female ; Gene Expression Regulation ; Humans ; Inflammation/genetics ; Inflammation/pathology ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/pathology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Mice, SCID ; Myeloid Progenitor Cells/metabolism ; NF-kappa B/genetics ; TNF Receptor-Associated Factor 6/genetics ; TNF Receptor-Associated Factor 6/metabolism ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
مستخلص: 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.
(© 2020 by The American Society of Hematology.)
التعليقات: Comment in: Blood. 2020 Jan 16;135(3):155-156. (PMID: 31945151)
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معلومات مُعتمدة: P30 CA033572 United States CA NCI NIH HHS; P50 CA107399 United States CA NCI NIH HHS; R01 AI125615 United States AI NIAID NIH HHS; R01 CA213131 United States CA NCI NIH HHS
المشرفين على المادة: 0 (MIRN146 microRNA, human)
0 (MicroRNAs)
0 (Mirn146 microRNA, mouse)
0 (NF-kappa B)
0 (TNF Receptor-Associated Factor 6)
تواريخ الأحداث: Date Created: 20191206 Date Completed: 20200420 Latest Revision: 20210202
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC6966933
DOI: 10.1182/blood.2019002045
PMID: 31805184
قاعدة البيانات: MEDLINE
الوصف
تدمد:1528-0020
DOI:10.1182/blood.2019002045