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MicroRNA in DNMT3A-mutant AML [miRNA-Seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE168509 | GEO | 2022/07/31

REPOSITORIES: GEO

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R848 treated DNMT3A-mutant AML [RNA-seq]

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

Screening microRNA-196 targets in 11q23-translocation acute myeloid leukemia reveal mechanisms maintaining leukemia stemness with therapeutic potential [RNA-seq]

Project description:microRNA are aberrantly expressed in acute myeloid leukemia (AML), and clinically may have diagnostic, prognostic, and therapeutic value. We identify one such microRNA, miR-196b, is essential for MLL-AF9 leukemia initiation and maintenance. To discover how miR-196b contributes to leukemogenesis, we utilized multiple unbiased approaches that identified and functionally screened miR-196b target activity in AML. Our studies resolved how conflicting networks of miRNA-regulated targets are integrated during leukemogenesis. This work uncovered two miR-196b direct targets, the cell cycle regulator Cdkn1b (p27Kip1) and Polycomb group member Phc2, that independently cooperate with MLL-AF9 to promote leukemogenesis by regulating stem cell transcriptional programs. Finally, we found that therapeutic disruption of miR-196b direct targeting of Cdkn1b suppresses leukemogenesis.

2018-06-29 | GSE75842 | GEO

Screening microRNA-196 targets in 11q23-translocation acute myeloid leukemia reveal mechanisms maintaining leukemia stemness with therapeutic potential [Gene 1.0 ST]

2018-06-29 | GSE75841 | GEO

A coordinated function of lncRNA HOTTIP and miRNA-196b underpinning leukemogenesis by targeting Fas signaling

Project description:MicroRNAs (miRNAs) may modulate more than 60% of human coding genes and act as negative regulators, while long non-coding RNAs (lncRNAs) regulate gene expression on multiple levels by interacting with chromatin, functional proteins, and RNAs such as mRNAs and microRNAs. However, the crosstalk between lncRNA HOTTIP and miRNAs in leukemogenesis remains elusive. Using combined integrated analyses of global miRNA expression profiling and state-of-the-art genomic analyses of chromatin such as ChIRP seq., (genome wide HOTTIP binding analysis), ChIP-seq., and ATAC-seq., we found that miRNA genes are directly controlled by HOTTIP. Specifically, the HOX cluster miRNAs (miR-196a, miR-196b, miR-10a and miR-10b), located cis & trans, were most dramatically regulated and significantly decreased in HOTTIP–/– AML cells. HOTTIP bound to the miR- 196b promoter, and HOTTIP deletion reduced chromatin accessibility and enrichment of active histone modifications at HOX cluster associated miRNAs in AML cells, while reactivation of HOTTIP restored miR gene expression and chromatin accessibility in the CTCF-boundary-attenuated AML cells. Inactivation of HOTTIP or miR-196b promotes apoptosis by altering the chromatin signature at the FAS promoter and increasing FAS expression. Transplantation of miR-196b knockdown MOLM13 cells in NSG mice increased overall survival compared to wild-type cells. Thus, HOTTIP remodels the chromatin architecture around miRNAs to promote their transcription, consequently repressing tumor suppressors and promoting leukemogenesis.

2022-09-14 | GSE182601 | GEO

Affymetrix gene arrays of leukemic BM samples from 24 mice including 9 primary

Project description:To identify such targets of leukemia-related miRNAs such as miR-196b, we conducted Affymetrix gene arrays of leukemic BM samples from 24 mice including 9 primary (including 3 each of negative control, MLL-AF9, and miR-196b+MLL-AF9) and 15 secondary (including 3 negative control, 6 MLL-AF9, and 6 miR-196b+MLL-AF9) recipient mice A total of 24 mouse bone marrow samples including 9 primary (including 3 each of negative control, MLL-AF9, and miR-196b+MLL-AF9) and 15 secondary (including 3 negative control, 6 MLL-AF9, and 6 miR-196b+MLL-AF9) obtained from the in vivo mouse bone marrow reconstitution assays were analyzed by use of Affymetrix GeneChip Mouse Gene 1.0 ST Array (Affymetirx, Santa Clara, CA)

2012-08-09 | E-GEOD-34185 | biostudies-arrayexpress

Affymetrix gene arrays of leukemic BM samples from 24 mice including 9 primary

2012-08-10 | GSE34185 | GEO

MiR-196b is epigenetically silenced during the pre-malignant stage of lung carcinogenesis

Project description:MicroRNA silencing by promoter hypermethylation may represent a mechanism by which lung cancer develops and progresses, but the microRNAs involved during malignant transformation are unknown. We previously established a model of pre-malignant lung cancer wherein we treated human bronchial epithelial cells (HBEC) with low doses of tobacco carcinogens. Here, we demonstrate that next-generation sequencing of carcinogen-transformed HBECs treated with the demethylating agent 5-aza-2'deoxycytidine revealed miR-196b and miR-34c-5p to be epigenetic targets. Bisulfite sequencing confirmed dense promoter hypermethylation indicative of silencing in multiple malignant cell lines and primary tumors. Chromatin immunoprecipitation studies further demonstrated an enrichment in repressive histone marks on the miR-196b promoter during HBEC transformation. Restoration of miR-196b expression by transfecting transformed HBECs with specific mimics led to cell cycle arrest mediated in part through transcriptional regulation of the FOS oncogene, and miR-196b re-expression also significantly reduced the growth of tumor xenografts. Luciferase assays demonstrated that forced expression of miR-196b inhibited the FOS promoter and AP-1 reporter activity. Finally, a case-control study revealed that methylation of miR-196b in sputum was strongly associated with lung cancer (OR = 4.7, p<0.001). Collectively, these studies highlight miR-196b as a tumor suppressor whose silencing early in lung carcinogenesis may provide a selective growth advantage to pre-malignant cells. Targeted delivery of miR-196b could therefore serve as a preventive or therapeutic strategy for the management of lung cancer. HBEC2MBT and H1975 were transiently transfected with a miR-196b mimic and subjected to array-based genome-wide gene expression profiling 48 hours post transfection.

2016-09-09 | GSE79987 | GEO

MiR-196b is epigenetically silenced during the pre-malignant stage of lung carcinogenesis

2016-09-09 | GSE79982 | GEO

MicroRNA-196b-5p is a prognostic factor in colorectal cancer patients and influences cancer cell migration and metastases formation through regulation of HOXB7 and GalNT5

Project description:Background: MicroRNA-196b-5p (miR-196b-5p) has been previously involved in carcinogenesis, though its role in colorectal cancer (CRC) patients and biology remains controversially. In our current study, we systematically explored the clinical significance and biological relevance of miR-196b-5p, as well as the underlying molecular mechanisms regulated by miR-196b-5p in colorectal cancer. Methods: In this study, we measured miR-196b-5p expression by quantitative RT-PCR and explored its prognostic value in two independent patient cohorts of 292 CRC patients. In a panel of CRC cell lines, using transient and stable gain and loss of function experiments, we evaluated the impact on in vitro proliferation, chemo-sensitivity and migration/invasion as well as in vivo metastases-formation. The molecular mode of action was characterized by mRNA transcriptome profiling, target prediction tools, luciferase-interaction assays, and pheno-copy gene knock-down experiments for potential target genes. Results: Our clinical data indicate that low levels of miR-196b-5p in CRC are significantly associated with metastatic disease and poor patient outcome in both independent cohorts (p<0.05). A loss of function of miR-196b-5p led to increased cancer cell migration/invasion and metastases formation, which can be partly explained by direct interaction with HOXB7 and GalNT5 mRNA, which both of them influence CRC cell migration. Conclusion: In conclusion, our data suggest that low levels of miR-196b-5p are associated with poor prognosis in CRC. MiR-196b-5p has an effect on CRC progression through genes important for cancer cell migration and metastases.

2017-01-01 | GSE86575 | GEO

BMSC-derived exosomal miR-27a-3p and miR-196b-5p regulate bone remodeling in ovariectomized rats

Project description:BMSC-derived exosomes from ovariectomized rats (OVX-Exo) and sham-operated rats (Sham-Exo) were co-cultured with bone marrow-derived macrophages to study their effects on osteoclast differentiation. Next-generation sequencing was utilized to identify the differentially expressed miRNAs (DE-miRNAs) in OVX-Exo and Sham-Exo, while target genes were analyzed using bioinformatics. The regulatory effects of miR-27a-3p and miR-196b-5p on osteogenic differentiation of BMSCs and osteoclast differentiation were verified by gain-of-function and loss-of-function analyses.Osteoclast differentiation was significantly enhanced in the OVX-Exo treatment group compared to the Sham-Exo group. Twenty DE-miRNAs were identified in OVX-Exo and Sham-Exo, among which miR-27a-3p and miR-196b-5p promoted the expressions of osteogenic genes in BMSCs. In contrast, knockdown of miR-27a-3p and miR-196b-5p increased the expressions of osteoclastic genes in osteoclasts. These 20 DE-miRNAs were found to target 11435 mRNAs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that these target genes were involved in several biological processes and osteoporosis-related signaling pathways.

2022-07-07 | GSE197085 | GEO

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