FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2551034811> ?p ?o ?g. }

• W2551034811 abstract "Abstract Abstract 3463 Epigenetic and apoptosis-regulating mechanisms have been implicated as critical factors contributing to the progression from myelodysplastic syndromes (MDS) to secondary acute myeloid leukemia (AML). However, the exact molecular mechanisms and genes involved in disease evolution have not been identified yet. We screened for epigenetically regulated pro-apoptotic effector molecules in neoplastic cells in patients with MDS (n=50) and AML (n=30). Among a series of potential regulators, we identified FAS (CD95) as an epigenetically regulated critical death regulator in neoplastic cells. As assessed by qPCR, bone marrow cells obtained from patients with low risk MDS were found to display high levels of FAS, whereas FAS mRNA levels were lower or undetectable in patients with advanced MDS (with excess of blasts) or secondary AML. Moreover, we were able to show by multicolor flow cytometry that CD34+/CD38+ progenitor cells and CD34+/CD38- stem cells in MDS and AML display measurable FAS (CD95) on their surface, with slightly higher levels detectable in progenitor cells in low risk MDS compared to high risk MDS and secondary AML. Methylation-specific PCR and qPCR revealed that the FAS-promoter is hypermethylated in primary AML cells as well as in various AML cell lines including KG1 and HL60 thus repressing mRNA-synthesis. In addition, we found that exposure to 5-Azacytidine or Decitabine leads to demethylation of CpG-rich regions closest to the transcription starting sites, and thus to re-expression of FAS in AML cells. In vitro-targeting of AML cells by demethylating drugs was also found to revert epigenetic inactivation of other tumor suppressor genes such as CDKN2B (P15), CDKN2A (P16), ESR1 (estrogen-receptor alpha), with subsequent normalization of mRNA expression levels. Next, we asked whether CD95 acts as a critical death regulator involved in drug-induced apoptosis in neoplastic cells. In these experiments, both demethylating agents, 5-Azacytidine or Decitabine, were found to induce dose-dependent apoptosis and growth inhibition in primary AML cells, primary MDS cells, and in all AML cell lines examined. Drug-induced apoptosis in AML cells was accompanied by activation of caspase 8 and caspase 3 as well as increased expression of proapoptotic FAS/CD95 as determined by qPCR, Western blotting, and flow cytometry. Moreover, both drugs were found to induce expression of the FAS-ligand and DAPK1 in neoplastic cells. We then applied a siRNA against FAS. The siRNA-induced knock-down of FAS was found to block drug-induced FAS expression and FAS-induced apoptosis in KG1 cells and HL60 cells. In conclusion, our data show that FAS is hypermethylated in neoplastic cells in patients with advanced MDS and AML, that demethylating agents lead to re-expression of FAS, and that drug-induced FAS expression mediates apoptosis in leukemic cells. As FAS is also expressed on neoplastic stem cells, these observations may have clinical implications and may explain beneficial effects seen with 5-Azacytidine or Decitabine in patients with advanced MDS. Disclosures: Valent: Novartis: Consultancy, Honoraria, Research Funding." @default.
• W2551034811 created "2016-11-30" @default.
• W2551034811 creator A5002559298 @default.
• W2551034811 creator A5006306448 @default.
• W2551034811 creator A5023762221 @default.
• W2551034811 creator A5030163841 @default.
• W2551034811 creator A5043678326 @default.
• W2551034811 creator A5052025914 @default.
• W2551034811 creator A5052731075 @default.
• W2551034811 creator A5055044824 @default.
• W2551034811 creator A5055484321 @default.
• W2551034811 creator A5056600574 @default.
• W2551034811 creator A5083642522 @default.
• W2551034811 creator A5086011150 @default.
• W2551034811 date "2011-11-18" @default.
• W2551034811 modified "2023-09-28" @default.
• W2551034811 title "5-Azacytidine and Decitabine Induce Demethylation and Re-Expression of FAS (CD95) and Promote Apoptosis in Neoplastic Cells in Acute Myeloid Leukemia (AML)," @default.
• W2551034811 doi "https://doi.org/10.1182/blood.v118.21.3463.3463" @default.
• W2551034811 hasPublicationYear "2011" @default.
• W2551034811 type Work @default.
• W2551034811 sameAs 2551034811 @default.
• W2551034811 citedByCount "1" @default.
• W2551034811 countsByYear W25510348112013 @default.
• W2551034811 crossrefType "journal-article" @default.
• W2551034811 hasAuthorship W2551034811A5002559298 @default.
• W2551034811 hasAuthorship W2551034811A5006306448 @default.
• W2551034811 hasAuthorship W2551034811A5023762221 @default.
• W2551034811 hasAuthorship W2551034811A5030163841 @default.
• W2551034811 hasAuthorship W2551034811A5043678326 @default.
• W2551034811 hasAuthorship W2551034811A5052025914 @default.
• W2551034811 hasAuthorship W2551034811A5052731075 @default.
• W2551034811 hasAuthorship W2551034811A5055044824 @default.
• W2551034811 hasAuthorship W2551034811A5055484321 @default.
• W2551034811 hasAuthorship W2551034811A5056600574 @default.
• W2551034811 hasAuthorship W2551034811A5083642522 @default.
• W2551034811 hasAuthorship W2551034811A5086011150 @default.
• W2551034811 hasConcept C10205521 @default.
• W2551034811 hasConcept C104317684 @default.
• W2551034811 hasConcept C150194340 @default.
• W2551034811 hasConcept C190283241 @default.
• W2551034811 hasConcept C190727270 @default.
• W2551034811 hasConcept C201750760 @default.
• W2551034811 hasConcept C203014093 @default.
• W2551034811 hasConcept C2776239401 @default.
• W2551034811 hasConcept C2778461978 @default.
• W2551034811 hasConcept C2778729363 @default.
• W2551034811 hasConcept C2779277951 @default.
• W2551034811 hasConcept C2779282312 @default.
• W2551034811 hasConcept C2780007613 @default.
• W2551034811 hasConcept C2780235182 @default.
• W2551034811 hasConcept C2780817109 @default.
• W2551034811 hasConcept C28328180 @default.
• W2551034811 hasConcept C3031857 @default.
• W2551034811 hasConcept C31573885 @default.
• W2551034811 hasConcept C502942594 @default.
• W2551034811 hasConcept C54355233 @default.
• W2551034811 hasConcept C86803240 @default.
• W2551034811 hasConcept C95444343 @default.
• W2551034811 hasConceptScore W2551034811C10205521 @default.
• W2551034811 hasConceptScore W2551034811C104317684 @default.
• W2551034811 hasConceptScore W2551034811C150194340 @default.
• W2551034811 hasConceptScore W2551034811C190283241 @default.
• W2551034811 hasConceptScore W2551034811C190727270 @default.
• W2551034811 hasConceptScore W2551034811C201750760 @default.
• W2551034811 hasConceptScore W2551034811C203014093 @default.
• W2551034811 hasConceptScore W2551034811C2776239401 @default.
• W2551034811 hasConceptScore W2551034811C2778461978 @default.
• W2551034811 hasConceptScore W2551034811C2778729363 @default.
• W2551034811 hasConceptScore W2551034811C2779277951 @default.
• W2551034811 hasConceptScore W2551034811C2779282312 @default.
• W2551034811 hasConceptScore W2551034811C2780007613 @default.
• W2551034811 hasConceptScore W2551034811C2780235182 @default.
• W2551034811 hasConceptScore W2551034811C2780817109 @default.
• W2551034811 hasConceptScore W2551034811C28328180 @default.
• W2551034811 hasConceptScore W2551034811C3031857 @default.
• W2551034811 hasConceptScore W2551034811C31573885 @default.
• W2551034811 hasConceptScore W2551034811C502942594 @default.
• W2551034811 hasConceptScore W2551034811C54355233 @default.
• W2551034811 hasConceptScore W2551034811C86803240 @default.
• W2551034811 hasConceptScore W2551034811C95444343 @default.
• W2551034811 hasLocation W25510348111 @default.
• W2551034811 hasOpenAccess W2551034811 @default.
• W2551034811 hasPrimaryLocation W25510348111 @default.
• W2551034811 hasRelatedWork W104615960 @default.
• W2551034811 hasRelatedWork W1694703176 @default.
• W2551034811 hasRelatedWork W1976117156 @default.
• W2551034811 hasRelatedWork W1976762367 @default.
• W2551034811 hasRelatedWork W2131183720 @default.
• W2551034811 hasRelatedWork W2369251668 @default.
• W2551034811 hasRelatedWork W2405320342 @default.
• W2551034811 hasRelatedWork W2553946514 @default.
• W2551034811 hasRelatedWork W2555894919 @default.
• W2551034811 hasRelatedWork W2559935654 @default.
• W2551034811 hasRelatedWork W2564711661 @default.
• W2551034811 hasRelatedWork W2606219893 @default.
• W2551034811 hasRelatedWork W2735852500 @default.
• W2551034811 hasRelatedWork W2741646465 @default.
• W2551034811 hasRelatedWork W2746022227 @default.
• W2551034811 hasRelatedWork W2786434754 @default.
• W2551034811 hasRelatedWork W2895922378 @default.

• next