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Decreased SATB1 expression promotes AML cell proliferation through NF-κB activation

ABSTRACT: Global gene expression profiles were analyzed in HL-60 cells with SATB1 knockdown to investigate the mechanisms underlying the regulation of AML cell growth by SATB1.Genes that displayed two-fold up-regulation or 0.5-fold down-regulation in expression in comparisons were selected for further analyses. Arrays with poor quality according to the manufacturer's recommendations were excluded from further analysis.We found the differentially expressed genes were involved in NF-κB, MAPK and PI3K/Akt signaling pathways. Nuclear NF-κB p65 levels were significantly increased in SATB1 depleted HL-60 cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE131247 | GEO | 2019/05/16

REPOSITORIES: GEO

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Project description:NF-κB is a key regulator of inflammation and cancer progression, with important role in leukemogenesis. Despite therapeutic potential, targeting NF-κB using pharmacologic inhibitors proved challenging. Here, we describe a myeloid cell-selective NF-κB inhibitor using miR146a mimic oligonucleotide conjugated to a scavenger receptor (SR)/Toll-like receptor 9 (TLR9) agonist (C-miR146a). Unlike an unconjugated miR-146a, C-miR146a was rapidly internalized and delivered to cytoplasm of target myeloid cells and leukemic cells. C-miR146a reduced expression of classic miR-146a targets, IRAK1 and TRAF6, thereby blocking NF-κB activation in target cells. Intravenous injections of C-miR146a mimic to miR-146-deficient mice prevented excessive NF-κB activation in myeloid cells, thereby alleviating 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 (CRS). Systemic administration of C-miR146a oligonucleotide alleviated human monocyte-dependent release of IL-1 and IL-6 in xenotransplanted B-cell lymphoma model without affecting CD19-specific CAR T-cell antitumor activity. Beyond anti-inflammatory functions, miR146a is a known tumor suppressor commonly deleted or expressed at reduced levels in human myeloid leukemia. Using TCGA AML dataset, we found inverse correlation of miR-146 levels with NF-κB-related genes and with patients’ survival. Correspondingly, C-miR146a induced cytotoxic effects in human MDSL, HL-60 and MV4-11 leukemia cells in vitro. The repeated intravenous administration of C-miR146a inhibited expression of NF-κB target genes and thereby thwarted progression of disseminated HL-60 leukemia. Our results demonstrate potential of using myeloid cell-targeted miR146a mimics for treatment of inflammatory and myeloproliferative disorders. NF-κB is a key regulator of inflammation and cancer progression, with important role in leukemogenesis. Despite therapeutic potential, targeting NF-κB using pharmacologic inhibitors proved challenging. Here, we describe a myeloid cell-selective NF-κB inhibitor using miR146a mimic oligonucleotide conjugated to a scavenger receptor (SR)/Toll-like receptor 9 (TLR9) agonist (C-miR146a). Unlike an unconjugated miR-146a, C-miR146a was rapidly internalized and delivered to cytoplasm of target myeloid cells and leukemic cells. C-miR146a reduced expression of classic miR-146a targets, IRAK1 and TRAF6, thereby blocking NF-κB activation in target cells. Intravenous injections of C-miR146a mimic to miR-146-deficient mice prevented excessive NF-κB activation in myeloid cells, thereby alleviating 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 (CRS). Systemic administration of C-miR146a oligonucleotide alleviated human monocyte-dependent release of IL-1 and IL-6 in xenotransplanted B-cell lymphoma model without affecting CD19-specific CAR T-cell antitumor activity. Beyond anti-inflammatory functions, miR146a is a known tumor suppressor commonly deleted or expressed at reduced levels in human myeloid leukemia. Using TCGA AML dataset, we found inverse correlation of miR-146 levels with NF-κB-related genes and with patients’ survival. Correspondingly, C-miR146a induced cytotoxic effects in human MDSL, HL-60 and MV4-11 leukemia cells in vitro. The repeated intravenous administration of C-miR146a inhibited expression of NF-κB target genes and thereby thwarted progression of disseminated HL-60 leukemia. Our results demonstrate potential of using myeloid cell-targeted miR146a mimics for treatment of inflammatory and myeloproliferative disorders.

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Decreased SATB1 expression promotes AML cell proliferation through NF-κB activation

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