MiR-196b-TLR7/8 signaling axis regulates innate immune signaling and myeloid maturation in DNMT3A-mutant AML
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ABSTRACT:
PROVIDER: PRJNA707593 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13786104_1.fastq.gz | Fastqsanger.gz | |||
| SRR13786104_2.fastq.gz | Fastqsanger.gz | |||
| SRR13786105_1.fastq.gz | Fastqsanger.gz | |||
| SRR13786105_2.fastq.gz | Fastqsanger.gz | |||
| SRR13786108_1.fastq.gz | Fastqsanger.gz |
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Project description:microRNA (miRNA or miR) are aberrantly expressed in acute myeloid leukemia (AML), and clinically may have diagnostic, prognostic, and therapeutic value. We identify miR-196b, is overexpressed in high-risk subset of DNMT3A-mutant AML and its activity is important to maintain a differentiation block and limit innate immune signaling pathways in AML. We interrogated previously published experimentally defined and computationally predicated miR-196b targets demonstrating that miR-196b regulates Toll-like Receptor Signaling. This work uncovered that miR-196b represses TLR7/8 activation and innate immune signaling in AML and that TLR7/8 activates a Stat1 transcriptional response associated with induced co-stimulatory molecule expression on the surface of AML-derived monocytes and dendritic-like cells.
2022-07-31 | GSE168509 | GEO
Project description:microRNA (miRNA or miR) are aberrantly expressed in acute myeloid leukemia (AML), and clinically may have diagnostic, prognostic, and therapeutic value. We identify miR-196b, is overexpressed in high-risk subset of DNMT3A-mutant AML and its activity is important to maintain a differentiation block and limit innate immune signaling pathways in AML. We interrogated previously published experimentally defined and computationally predicated miR-196b targets demonstrating that miR-196b regulates Toll-like Receptor Signaling. This work uncovered that miR-196b represses TLR7/8 activation and innate immune signaling in AML and that TLR7/8 activates a Stat1 transcriptional response associated with induced co-stimulatory molecule expression on the surface of AML-derived monocytes and dendritic-like cells.
2022-07-31 | GSE167571 | GEO
Project description:microRNA (miRNA or miR) are aberrantly expressed in acute myeloid leukemia (AML), and clinically may have diagnostic, prognostic, and therapeutic value. We identify miR-196b, is overexpressed in high-risk subset of DNMT3A-mutant AML and its activity is important to maintain a differentiation block and limit innate immune signaling pathways in AML. We interrogated previously published experimentally defined and computationally predicated miR-196b targets compared with genes differentially expressed in miR-196b-/-Dnmt3a/Flt3ITD AML versus Dnmt3a/Flt3ITD AML. This identified that miR-196b regulates Pou2f1 and Pou2f2 (Oct1 and Oct2) in Dnmt3a/Flt3-mutant AML.
2024-09-01 | GSE192639 | GEO
Project description:PurposeDNMT3A mutations confer a poor prognosis in acute myeloid leukemia (AML), but the molecular mechanisms downstream of DNMT3A mutations in disease pathogenesis are not completely understood, limiting targeted therapeutic options. The role of miRNA in DNMT3A-mutant AML pathogenesis is understudied.Experimental designDNA methylation and miRNA expression was evaluated in human AML patient samples and in Dnmt3a/Flt3-mutant AML mice. The treatment efficacy and molecular mechanisms of TLR7/8-directed therapies on DNMT3A-mutant AML were evaluated in vitro on human AML patient samples and in Dnmt3a/Flt3-mutant AML mice.ResultsmiR-196b is hypomethylated and overexpressed in DNMT3A-mutant AML and is associated with poor patient outcome. miR-196b overexpression in DNMT3A-mutant AML is important to maintain an immature state and leukemic cell survival through repression of TLR signaling. The TLR7/8 agonist resiquimod induces dendritic cell-like differentiation with costimulatory molecule expression in DNMT3A-mutant AML cells and provides a survival benefit to Dnmt3a/Flt3-mutant AML mice. The small molecule bryostatin-1 augments resiquimod-mediated AML growth inhibition and differentiation.ConclusionsDNMT3A loss-of-function mutations cause miRNA locus-specific hypomethylation and overexpression important for mutant DNMT3A-mediated pathogenesis and clinical outcomes. Specifically, the overexpression of miR-196b in DNMT3A-mutant AML creates a novel therapeutic vulnerability by controlling sensitivity to TLR7/8-directed therapies.
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Project description:To understand the pathogenesis of DNMT3A in acute monocytic leukemia (AML-M5), we identified genes that are expressed differently in leukemia cells from AML-M5 patients collected at diagnosis with DNMT3A mutations (6 cases) compared to those without the mutations (4 cases). Differences of expression level were observed in 889 out of 20,723 (4.3%) annotated genes by using Affymetrix microarray with 469 genes upregulated and 420 genes downregulated. Leukemia cells in bone marrow of acute monocytic leukemia patients were collected at diagnosis for RNA extraction and hybridization on Affymetrix microarrays. 6 cases of AML-M5 samples with DNMT3A mutations and 4 cases of AML-M5 samples wihtout DNMT3A mutations were used.
2011-02-12 | E-GEOD-27187 | biostudies-arrayexpress
Project description:miR196b-/- DNMT3A-mutant AML [RNA-seq]
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Project description:DNA methyltransferases DNMT3A- and DNMT3B-mediated de novo DNA methylation critically regulates epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) promote macro-oligomer formation, leading to aberrant DNA methylation that in turn contributes to pathogenesis of acute myeloid leukemia (AML). However, the molecular basis underlying the hotspot mutation-induced functional mis-regulation of DNMT3A remains unclear. Here, we report the crystal structure of DNMT3A methyltransferase (MTase) domain, revealing a molecular basis for its DNMT3B-distinct oligomerization behavior. Introducing DNMT3B-converting mutations to DNMT3A R882 mutants also led to structure determination of R882H- and R882C-mutated DNMT3A, which show enhanced intermolecular contacts than wild-type DNMT3A. Consistently, our in vitro and genomic DNA methylation analyses reveal that the DNMT3B-converting mutations eliminate the gain-of-function effect of the DNMT3A R882 mutations in cells. Together, this study provides mechanistic insights into DNMT3A R882 mutation-triggered aberrant oligomerization and DNA hypomethylation in AML, with important implications in cancer therapy.
2023-12-31 | GSE225828 | GEO
Project description:The debilitating autoimmune disease Systemic Lupus Erythematosus (SLE) is closely associated with Toll-like receptor (TLR) 7 and type I interferon (IFN) activity in humans and in murine SLE-like disease. Two central manifestations of SLE affect the myeloid lineage of the immune system, myeloid expansion and anemia. Yet, whether these symptoms are linked and the role of TLR7 and/or type I IFN in these processes is unclear. Here we show that TLR7 signaling promotes cell-autonomous, phosphoinositide 3-kinase (PI3K)- and mammalian target of rapamycin (mTOR)-dependent macrophage development from the common myeloid progenitor (CMP). Strikingly, this TLR7-driven macrophage development requires and is enhanced by type I IFN. Genome-wide transcriptional profiling and functional studies demonstrated that TLR7 promoted the expression of Spic, the master regulator of splenic red pulp macrophages (RPM) and preferential development of hemophagocytic RPM-like cells from CMP in vitro. We found increased incidence of RPM-like cells in vivo in a mouse model of SLE caused by TLR7 overexpression, which correlated with decreased red blood cell (RBC) count and anemia. These findings demonstrate a mechanism by which TLR7 signaling promotes anemia that is of clinical significance in SLE, other rheumatological diseases and chronic viral infections. This work also identifies a previously unknown molecular pathway by which TLR signaling and type I IFN synergize to promote myeloid development from hematopoietic progenitors. CMP were sorted from the bone marrow of wild-type C57BL/6 mice, cultured with SCF+R848 or SCFr+MCSF, and CD11b+F4/80+ macrophages sorted after 5 days, n=3 per group
2016-07-01 | E-GEOD-70520 | biostudies-arrayexpress
Project description:DNA methyltransferases DNMT3A- and DNMT3B-mediated de novo DNA methylation critically regulates epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) promote macro-oligomer formation, leading to aberrant DNA methylation that in turn contributes to pathogenesis of acute myeloid leukemia (AML). However, the molecular basis underlying the hotspot mutation-induced functional mis-regulation of DNMT3A remains unclear. Here, we report the crystal structure of DNMT3A methyltransferase (MTase) domain, revealing a molecular basis for its DNMT3B-distinct oligomerization behavior. Introducing DNMT3B-converting mutations to DNMT3A R882 mutants also led to structure determination of R882H- and R882C-mutated DNMT3A, which show enhanced intermolecular contacts than wild-type DNMT3A. Consistently, our in vitro and genomic DNA methylation analyses reveal that the DNMT3B-converting mutations eliminate the gain-of-function effect of the DNMT3A R882 mutations in cells. Together, this study provides mechanistic insights into DNMT3A R882 mutation-triggered aberrant oligomerization and DNA hypomethylation in AML, with important implications in cancer therapy.
2023-12-31 | GSE226062 | GEO
Project description:R848 treated DNMT3A-mutant AML [RNA-seq]
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