MafB enhances oncogenic Notch signaling in T-ALL [Microarray]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE104991 | GEO | 2017/10/17
SECONDARY ACCESSION(S): PRJNA414388
REPOSITORIES: GEO
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Project description:MafB enhances oncogenic Notch signaling in T-ALL [Microarray]
| PRJNA414388 | ENA
Project description:MafB enhances oncogenic Notch signaling in T-ALL
| PRJNA414384 | ENA
Project description:Activating mutations in the gene encoding the cell-cell contact signaling protein Notch1 are common in human T cell acute lymphoblastic leukemias (T-ALLs). However, expressing Notch1 mutant alleles in mice fails to efficiently induce the development of leukemia. We performed a gain-of-function screen to identify proteins that enhanced signaling by leukemia-associated Notch1 mutants. The transcription factors MAFB and ETS2 emerged as candidates that individually enhanced Notch1 signaling, and when coexpressed, they synergistically increased signaling to an extent similar to that induced by core components of the Notch transcriptional complex. In mouse models of T-ALL, MAFB enhanced leukemogenesis by the naturally occurring Notch1 mutants, decreased disease latency, and increased disease penetrance. Decreasing MAFB abundance in mouse and human T-ALL cells reduced the expression of Notch1 target genes, including MYC and HES1, and sustained MAFB knockdown impaired T-ALL growth in a competitive setting. MAFB bound to ETS2 and interacted with the acetyltransferases PCAF and P300, highlighting its importance in recruiting coactivators that enhance Notch1 signaling. Together, these data identify a mechanism for enhancing the oncogenic potential of weak Notch1 mutants in leukemia models, and they reveal the MAFB-ETS2 transcriptional axis as a potential therapeutic target in T-ALL.
| S-EPMC5885022 | biostudies-literature
Project description:MafB enhances oncogenic Notch signaling in T-ALL [ChIP-Seq]
| PRJNA414387 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-10-17 | GSE104993 | GEO
Project description:MafB effect on H3K27ac in T6E cell line
2017-10-17 | GSE104992 | GEO
Project description:Loss or damage to the mandible due to trauma, treatment of oral malignancies, and other diseases is currently treated using bone grafting techniques that suffer from numerous shortcomings and contraindications. Zebrafish naturally heal large injuries to their mandibular bone, and thus offer an opportunity to understand how to boost intrinsic healing ability. Using a novel her6:mCherry Notch reporter, we show that canonical Notch signaling is induced during the initial stages of cartilage callus formation in both mesenchymal cells and chondrocytes. We also show that modulation of Notch signaling during the initial postoperative period results in lasting changes to regenerate bone quantity one month later. Notch signaling is required for mandibular bone healing, as pharmacological inhibition of Notch signaling blocks cartilage callus formation and results in non-union. Conversely, conditional transgenic activation of Notch signaling accelerates regenerative ossification. Mechanistically, we report that postoperative Notch signaling regulates multiple phases of chondroid regeneration and patterns callus metabolic landscape. Given conserved functions of Notch signaling in bone repair across vertebrates, we propose that targeted activation of Notch signaling during the early phases of bone healing may have therapeutic value.
2022-03-07 | PXD027280 | Pride
Project description:Soft tissue sarcomas (STS) are a heterogeneous group of tumors associated with poor clinical outcome. While a subset of STS are characterized by simple karyotypes and recurrent chromosomal translocations, the mechanisms driving cytogenetically complex sarcomas are largely unknown. Clinical evidence led us to partially inactivate Pten and p53 in the smooth muscle lineage of mice, which developed high-grade undifferentiated pleomorphic sarcomas (HGUPS), leiomyosarcomas (LMS) and carcinosarcomas (CS) that widely recapitulate the human disease, including the aberrant karyotype and metastatic behavior. Pten was found haploinsufficient whereas the wild-type allele of p53 invariably gained point mutations. Gene expression profile showed upregulated Notch signaling in PtenM-bM-^HM-^F/+p53M-bM-^HM-^F/+ tumors compared to Pten+/+p53M-bM-^HM-^F/+. Consistently, Pten silencing exacerbated the clonogenic and invasive potential of p53-deficient bone marrow-derived mouse mesenchymal stem cells and tumor cells, while activating the Notch pathway. Moreover, the increased oncogenic behavior of PtenM-bM-^HM-^F/+p53M-bM-^HM-^F/+ and shPten-transduced Pten+/+p53M-bM-^HM-^F/+ tumor cells was counteracted by treatment with a gamma secretase inhibitor (GSI), suggesting that the aggressiveness of those tumors can be attributed, at least in part, to enhanced Notch signaling. This study demonstrates a cooperative role for Pten and p53 suppression in complex karyotype sarcomas while establishing Notch as an important functional player in the crosstalk of these pathways during tumor progression. Our results highlight the importance of molecularly subclassifying high-grade sarcoma patients for targeted treatments. Compare PtenM-bM-^HM-^F/+p53M-bM-^HM-^F/+ to Pten+/+p53M-bM-^HM-^F/+ high-grade undifferentiated pleomorphic sarcomas (HGUPS) 4 PtenM-bM-^HM-^F/+p53M-bM-^HM-^F/+ were compared to 5 Pten+/+p53M-bM-^HM-^F/+ Keywords: Differential gene expression.
2013-01-01 | E-GEOD-42103 | biostudies-arrayexpress
Project description:Soft tissue sarcomas (STS) are a heterogeneous group of tumors associated with poor clinical outcome. While a subset of STS are characterized by simple karyotypes and recurrent chromosomal translocations, the mechanisms driving cytogenetically complex sarcomas are largely unknown. Clinical evidence led us to partially inactivate Pten and p53 in the smooth muscle lineage of mice, which developed high-grade undifferentiated pleomorphic sarcomas (HGUPS), leiomyosarcomas (LMS) and carcinosarcomas (CS) that widely recapitulate the human disease, including the aberrant karyotype and metastatic behavior. Pten was found haploinsufficient whereas the wild-type allele of p53 invariably gained point mutations. Gene expression profile showed upregulated Notch signaling in Pten∆/+p53∆/+ tumors compared to Pten+/+p53∆/+. Consistently, Pten silencing exacerbated the clonogenic and invasive potential of p53-deficient bone marrow-derived mouse mesenchymal stem cells and tumor cells, while activating the Notch pathway. Moreover, the increased oncogenic behavior of Pten∆/+p53∆/+ and shPten-transduced Pten+/+p53∆/+ tumor cells was counteracted by treatment with a gamma secretase inhibitor (GSI), suggesting that the aggressiveness of those tumors can be attributed, at least in part, to enhanced Notch signaling. This study demonstrates a cooperative role for Pten and p53 suppression in complex karyotype sarcomas while establishing Notch as an important functional player in the crosstalk of these pathways during tumor progression. Our results highlight the importance of molecularly subclassifying high-grade sarcoma patients for targeted treatments. Compare Pten∆/+p53∆/+ to Pten+/+p53∆/+ high-grade undifferentiated pleomorphic sarcomas (HGUPS)
2013-01-01 | GSE42103 | GEO
Project description:ARMMs (arrestin domain-containing protein 1 [ARRDC1]-mediated microvesicles) are extracellular vesicles that bud directly atthe plasma membrane. However, little is known about the physiological function of these vesicles. Here we report that secreted ARMMs contain active NOTCH receptors and mediate a non-canonical intercellular NOTCH signaling. Masss pectrometry of purified ARMMs identifiedNOTCH2 as a protein component of the vesicles. The NOTCH protein in ARMMs contains the critical intracellular region (NICD) that is required for its transcriptional activity in the nucleus. ARRDC1 overexpression increased the NOTCH2 incorporation into ARMMs. Conversely, CRISPR-mediated knockout of ARRDC1 dramatically reduced the amount of NOTCH2 in secreted ARMMs. The incorporation of NOTCH2 into ARMMs is facilitated by the ITCH E3 ligase and ADAM10, which are also secreted into ARMMs. We showed NOTCH2 in ARMMs delivered into recipient cells is further activated by γ-secretase cleavage to induce NOTCH-specific signaling in recipient cells. Together, our findings revealed a role for ARMMs in a novelNOTCH signaling pathway that acts in distance beyond direct cell-cell contact.
2017-10-11 | PXD006416 | Pride