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MicroRNA-146a modulates B-cell oncogenesis by regulating EGR1

ABSTRACT: miR-146a is a NF-κB induced microRNA that serves as a feedback regulator of this critical pathway. In mice, deficiency of miR-146a results in hematolymphoid cancer at advanced ages as a consequence of constitutive NF-κB activity. In this study, we queried whether the deficiency of miR-146a contributes to B-cell oncogenesis. Combining miR-146a deficiency with transgenic expression of c-Myc led to the development of highly aggressive B-cell malignancies. Mice transgenic for c-Myc and deficient for miR-146a were characterized by significantly shortened survival, increased lymph node involvement, differential involvement of the spleen and a mature B-cell phenotype. High-throughput sequencing of the tumors revealed significant dysregulation of approximately 250 genes. Amongst these, the transcription factor Egr1 was consistently upregulated in mice deficient for miR-146a. Interestingly, transcriptional targets of Egr1 were enriched in both the high-throughput dataset and in a larger set of miR-146a-deficient tumors. miR-146a overexpression led to downregulation of Egr1 and downstream targets with concomitant decrease in cell growth. Direct targeting of the human EGR1 by miR-146a was seen by luciferase assay. Together our findings illuminate a bona fide role for miR-146a in the modulation of B-cell oncogenesis and reveal the importance of understanding microRNA function in a cell- and disease-specific context.

ORGANISM(S): Mus musculus

PROVIDER: GSE67113 | GEO | 2016/03/20

SECONDARY ACCESSION(S): PRJNA278976

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.

Project description:Diabetes is a metabolic disorder characterized by fasting hyperglycemia and impaired glucose tolerance. Laboratory and population studies have shown that inorganic arsenic (iAs) can impair these pathways. Other metals including cadmium (Cd) and manganese (Mn) have also been linked to diabetes phenotypes. MicroRNAs, short non-coding RNAs that regulate gene expression, have emerged as potential drivers of metabolic dysfunction. MicroRNAs responsive to metal exposures in vitro have also been reported in independent studies to regulate insulin secretion in vivo. We hypothesize that microRNA dysregulation may associate with and possibly contribute to insulin secretion impairment upon exposure to iAs, Cd, or Mn. We exposed insulin secreting rat insulinoma cells to non-cytotoxic concentrations of iAs (1 µM), Cd (5 µM), and Mn (25 µM) for 24 h followed by small RNA sequencing to identify dysregulated microRNAs. RNA sequencing was then performed to further investigate changes in gene expression caused by iAs exposure. While all three metals significantly inhibited glucose-stimulated insulin secretion, high-throughput sequencing revealed distinct microRNA profiles specific to each exposure. One of the most significantly upregulated microRNAs post-iAs treatment is miR-146a (~ + 2-fold), which is known to be activated by nuclear factor κB (NF-κB) signaling. Accordingly, we found by RNA-seq analysis that genes upregulated by iAs exposure are enriched in the NF-κB signaling pathway and genes down-regulated by iAs exposure are enriched in miR-146a binding sites and are involved in regulating beta cell function. Notably, iAs exposure caused a significant decrease in the expression of Camk2a, a calcium-dependent protein kinase that regulates insulin secretion, has been implicated in type 2 diabetes, and is a likely target of miR-146a. Further studies are needed to elucidate potential interactions among NF-kB, miR-146a, and Camk2a in the context of iAs exposure.

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MicroRNA-146a modulates B-cell oncogenesis by regulating EGR1

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