FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4231731036> ?p ?o ?g. }

• W4231731036 endingPage "5223" @default.
• W4231731036 startingPage "5223" @default.
• W4231731036 abstract "Abstract STAT5 proteins are transcription factors involved in the regulation of proliferation, apoptosis and differentiation. Upon ligand-mediated activation, phosphorylated STAT5A (pSTAT5A) and pSTAT5B form homo- or heterodimers, translocate to the nucleus and activate transcription. Recent data indicate an important role of un-phosphorylated STAT5 (uSTAT5) in the regulation of differentiation. For example, the presence of uStat5 shifts the balance toward the maintenance of leukemic stem cells, whereas genetic depletion of Stat5induced differentiation. Further, uSTAT5 has been shown to act as a repressor of megakaryocytic differentiation via restricting the access of ERG to its target genes. To further investigate the function of uSTAT5 in mammalian AML, we established several cell line models expressing doxycycline-inducible shRNA directed against either STAT5A or STAT5B. In uSTAT5-expressing AML cells targeting of STAT5A or STAT5B suppressed cell growth and induced differentiation. These effects were significantly stronger upon knockdown of STAT5B compared to STAT5A. Global RNA sequencing demonstrated enrichment of differentiation programs upon downregulation of uSTAT5B. To further explore the biological function of uSTAT5, we performed SILAC-based global proteomics after pulldown of either STAT5A or STAT5B. While uSTAT5A was found to be associated with proteins involved in RNA processing, uSTAT5B primarily co-precipitated with chromatin- and histone-binding proteins, like the transcriptional repressor ETV6 or the histone H3K4 demethylase KDM5C. To dissect the specific roles of pSTAT5B and uSTAT5B, we performed co-immunoprecipitation assay upon treatment of AML cells with GM-CSF or vehicle control. As expected, GM-CSF treatment caused strong phosphorylation of STAT5A/B, however, uSTAT5B-binding of ETV6 was almost completely abolished, indicating a specific association only with uSTAT5B. As depletion of uSTAT5B induced differentiation and uSTAT5B interacts with KDM5C and ETV6, we hypothesized that uSTAT5B prevents transcription of genes involved in differentiation. To address this question, we performed H3K4me3 ChIP-seq analysis in THP-1 cells upon knockdown of STAT5B. Downregulation of uSTAT5B caused strong accumulation of H3K4me3 at promoter regions of previously silenced genes. Finally, we wanted to investigate whether targeting of KDM5C can reverse disturbed differentiation in AML cells. Treatment with the KDM5 inhibitor CPI-455 significantly inhibited proliferation and induced apoptosis, but only in AML samples expressing uSTAT5B. In summary, our data provide evidence that uSTAT5B specifically blocks differentiation in AML cells via its interaction with KDM5C followed by repression of H3K4me3 at distinct promoter regions. Targeting of uSTAT5B or its interacting partners might represent an interesting novel strategy in AML therapy. Citation Format: Jakub Szybinski, Daniel Sasca, Jan Heidelberger, Karolin Klumb, Viral Shah, Anna Dolnik, Matthias Theobald, Lars Bullinger, Petra Beli, Thomas Kindler. Epigenetic silencing mediated by non-phosphorylated STAT5B prevents differentiation in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5223." @default.
• W4231731036 created "2022-05-12" @default.
• W4231731036 creator A5004269135 @default.
• W4231731036 creator A5005303780 @default.
• W4231731036 creator A5012146784 @default.
• W4231731036 creator A5023228789 @default.
• W4231731036 creator A5023814642 @default.
• W4231731036 creator A5036934797 @default.
• W4231731036 creator A5037380843 @default.
• W4231731036 creator A5040956966 @default.
• W4231731036 creator A5046034506 @default.
• W4231731036 creator A5054595414 @default.
• W4231731036 date "2019-07-01" @default.
• W4231731036 modified "2023-10-02" @default.
• W4231731036 title "Abstract 5223: Epigenetic silencing mediated by non-phosphorylated STAT5B prevents differentiation in acute myeloid leukemia" @default.
• W4231731036 doi "https://doi.org/10.1158/1538-7445.am2019-5223" @default.
• W4231731036 hasPublicationYear "2019" @default.
• W4231731036 type Work @default.
• W4231731036 citedByCount "0" @default.
• W4231731036 crossrefType "journal-article" @default.
• W4231731036 hasAuthorship W4231731036A5004269135 @default.
• W4231731036 hasAuthorship W4231731036A5005303780 @default.
• W4231731036 hasAuthorship W4231731036A5012146784 @default.
• W4231731036 hasAuthorship W4231731036A5023228789 @default.
• W4231731036 hasAuthorship W4231731036A5023814642 @default.
• W4231731036 hasAuthorship W4231731036A5036934797 @default.
• W4231731036 hasAuthorship W4231731036A5037380843 @default.
• W4231731036 hasAuthorship W4231731036A5040956966 @default.
• W4231731036 hasAuthorship W4231731036A5046034506 @default.
• W4231731036 hasAuthorship W4231731036A5054595414 @default.
• W4231731036 hasConcept C101762097 @default.
• W4231731036 hasConcept C104317684 @default.
• W4231731036 hasConcept C11960822 @default.
• W4231731036 hasConcept C134320426 @default.
• W4231731036 hasConcept C146777309 @default.
• W4231731036 hasConcept C148738053 @default.
• W4231731036 hasConcept C150194340 @default.
• W4231731036 hasConcept C153911025 @default.
• W4231731036 hasConcept C158448853 @default.
• W4231731036 hasConcept C167227067 @default.
• W4231731036 hasConcept C173396325 @default.
• W4231731036 hasConcept C190232843 @default.
• W4231731036 hasConcept C502942594 @default.
• W4231731036 hasConcept C54355233 @default.
• W4231731036 hasConcept C81885089 @default.
• W4231731036 hasConcept C83640560 @default.
• W4231731036 hasConcept C86339819 @default.
• W4231731036 hasConcept C86803240 @default.
• W4231731036 hasConcept C95444343 @default.
• W4231731036 hasConceptScore W4231731036C101762097 @default.
• W4231731036 hasConceptScore W4231731036C104317684 @default.
• W4231731036 hasConceptScore W4231731036C11960822 @default.
• W4231731036 hasConceptScore W4231731036C134320426 @default.
• W4231731036 hasConceptScore W4231731036C146777309 @default.
• W4231731036 hasConceptScore W4231731036C148738053 @default.
• W4231731036 hasConceptScore W4231731036C150194340 @default.
• W4231731036 hasConceptScore W4231731036C153911025 @default.
• W4231731036 hasConceptScore W4231731036C158448853 @default.
• W4231731036 hasConceptScore W4231731036C167227067 @default.
• W4231731036 hasConceptScore W4231731036C173396325 @default.
• W4231731036 hasConceptScore W4231731036C190232843 @default.
• W4231731036 hasConceptScore W4231731036C502942594 @default.
• W4231731036 hasConceptScore W4231731036C54355233 @default.
• W4231731036 hasConceptScore W4231731036C81885089 @default.
• W4231731036 hasConceptScore W4231731036C83640560 @default.
• W4231731036 hasConceptScore W4231731036C86339819 @default.
• W4231731036 hasConceptScore W4231731036C86803240 @default.
• W4231731036 hasConceptScore W4231731036C95444343 @default.
• W4231731036 hasIssue "13_Supplement" @default.
• W4231731036 hasLocation W42317310361 @default.
• W4231731036 hasOpenAccess W4231731036 @default.
• W4231731036 hasPrimaryLocation W42317310361 @default.
• W4231731036 hasRelatedWork W1983236475 @default.
• W4231731036 hasRelatedWork W2013150998 @default.
• W4231731036 hasRelatedWork W2060944726 @default.
• W4231731036 hasRelatedWork W2069313562 @default.
• W4231731036 hasRelatedWork W2097327869 @default.
• W4231731036 hasRelatedWork W2097751554 @default.
• W4231731036 hasRelatedWork W2557409806 @default.
• W4231731036 hasRelatedWork W2807017242 @default.
• W4231731036 hasRelatedWork W3008180407 @default.
• W4231731036 hasRelatedWork W4207009681 @default.
• W4231731036 hasVolume "79" @default.
• W4231731036 isParatext "false" @default.
• W4231731036 isRetracted "false" @default.
• W4231731036 workType "article" @default.