FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2979768788> ?p ?o ?g. }

• W2979768788 abstract "Abstract OBJECTIVES: Activating RAS mutations and over-expression of BCL-2 are prognostic features of myelodysplastic syndromes/acute myeloid leukemia (MDS/AML) transformation. Using NRASD12 and BCL-2, we created two distinct transplantable in vivo models of MDS and AML. Expression of hBCL-2 in a primitive compartment by MMTV-LTR results in a disease resembling human MDS with bone marrow blasts of 15% with increased apoptosis assayed by TUNEL on liver sections, whilst the myeloid MRP8 promoter induces a disease with characteristics of human AML with marrow blasts of up to 90% with liver apoptosis patterns similar to wild type. In MDS mice RAS and BCL-2 do not co-localize in the mitochondria, but localize to the plasma membrane, where active pro-apoptotic RAS is normally located, whereas in the AML disease RAS and BCL-2 co-localize in the mitochondria, where BCL-2 is normally found; consistent with its anti-apoptotic properties. We next examine the mouse hematopoietic FDCP-1 in vitro model with stable exogenous expression of NRASD12, hBCL-2 or NRASD12 and hBCL-2. Furthermore, we report the in vivo effects of the BH-3 mimetic inhibitor ABT-737. RESULTS: FDCP-1 lines demonstrate that whilst hBCL-2 alone prevents staurosporine-induced mitochondrial-dependent (caspase-9-mediated intrinsic) apoptosis, both NRAS-D12 and NRASD12/hBCL-2 cell lines were pro-apoptotic. No significant difference was observed in cell-death receptor (caspase-8-mediated extrinsic) apoptosis between the cell lines following pharmacological induction with Fas-ligand or TRAIL. Annexin-V/Propidium Iodide flow cytometry and caspase activity assays on hematopoietic primary cells from the mouse models recapitulated the findings; namely the MDS-model demonstrates increased caspase-9-mediated apoptosis (within the Lin−/Sca-1+/KIT+ (LSK) sub-population), whilst the AML-model illustrate anti-apoptotic activity. This is concordant with the signaling profile where phosphorylated AKT is reduced in the RAS-mediated MDS mice and active-AKT is increased in the BCL-2 mediated AML disease. Expanded leukemic stem cell LSK populations had increased hBCL-2 expression in the RAS-GTP complex in both MDS/AML diseases. Thus we suggest that this complex can be a specific target for therapy. When hBCL-2 is switched off with doxycycline in the conditional MDS mice, only partial reversal of the phenotype was observed as RAS recruits endogenous mouse BCL-2 to remain active; thus demonstrating the role of the complex in the disease. In order to target both human and mouse BCL-2 the efficacy of in vivo treatment with the specific BH-3 mimetic inhibitor ABT-737 was determined. We show that the treatment significantly reduced the progression of the disease, increased the peripheral blood platelet counts, decreased the bone marrow blast and cleared the tissue invasion in the MDS mice or reduced tissue infiltration of the AML. In vivo imaging by single-photon emission computed tomography (SPECT) using 99mTc-labelled Annexin-V shows that ABT-737 induces apoptosis of the blast cells that infiltrate the liver and the spleen of the treated mice, which was confirmed by TUNEL on liver sections. Additionally, ABT-737 can reduce the myeloid colony growth and the LSK expansion in these mice; whilst abrogating BCL-2:RAS-GTP complex formation illustrated via biochemical and confocal assays. CONCLUSION: This represents the first in vivo progression model of MDS/AML dependent on the formation of a BCL-2:RAS-GTP complex rescued by ABT-737 via intrinsic apoptosis and thus support the case for BH-3 mimetic therapy." @default.
• W2979768788 created "2019-10-18" @default.
• W2979768788 creator A5002316165 @default.
• W2979768788 creator A5008693390 @default.
• W2979768788 creator A5015390570 @default.
• W2979768788 creator A5022647201 @default.
• W2979768788 creator A5026162865 @default.
• W2979768788 creator A5026255816 @default.
• W2979768788 creator A5035774267 @default.
• W2979768788 creator A5042465065 @default.
• W2979768788 creator A5042472345 @default.
• W2979768788 creator A5051883204 @default.
• W2979768788 creator A5071787127 @default.
• W2979768788 creator A5079262854 @default.
• W2979768788 creator A5081072676 @default.
• W2979768788 creator A5081849224 @default.
• W2979768788 creator A5082894731 @default.
• W2979768788 creator A5083943894 @default.
• W2979768788 creator A5089732539 @default.
• W2979768788 creator A5069676249 @default.
• W2979768788 date "2008-11-16" @default.
• W2979768788 modified "2023-09-30" @default.
• W2979768788 title "ABT-737 Targets Intrinsic Apoptosis during Cooperation of BCL-2 and Oncogenic NRAS in An in Vivo Progression Model of Myelodysplasia/Acute Myeloid Leukaemia" @default.
• W2979768788 doi "https://doi.org/10.1182/blood.v112.11.848.848" @default.
• W2979768788 hasPublicationYear "2008" @default.
• W2979768788 type Work @default.
• W2979768788 sameAs 2979768788 @default.
• W2979768788 citedByCount "0" @default.
• W2979768788 crossrefType "journal-article" @default.
• W2979768788 hasAuthorship W2979768788A5002316165 @default.
• W2979768788 hasAuthorship W2979768788A5008693390 @default.
• W2979768788 hasAuthorship W2979768788A5015390570 @default.
• W2979768788 hasAuthorship W2979768788A5022647201 @default.
• W2979768788 hasAuthorship W2979768788A5026162865 @default.
• W2979768788 hasAuthorship W2979768788A5026255816 @default.
• W2979768788 hasAuthorship W2979768788A5035774267 @default.
• W2979768788 hasAuthorship W2979768788A5042465065 @default.
• W2979768788 hasAuthorship W2979768788A5042472345 @default.
• W2979768788 hasAuthorship W2979768788A5051883204 @default.
• W2979768788 hasAuthorship W2979768788A5069676249 @default.
• W2979768788 hasAuthorship W2979768788A5071787127 @default.
• W2979768788 hasAuthorship W2979768788A5079262854 @default.
• W2979768788 hasAuthorship W2979768788A5081072676 @default.
• W2979768788 hasAuthorship W2979768788A5081849224 @default.
• W2979768788 hasAuthorship W2979768788A5082894731 @default.
• W2979768788 hasAuthorship W2979768788A5083943894 @default.
• W2979768788 hasAuthorship W2979768788A5089732539 @default.
• W2979768788 hasConcept C109159458 @default.
• W2979768788 hasConcept C121608353 @default.
• W2979768788 hasConcept C153911025 @default.
• W2979768788 hasConcept C190283241 @default.
• W2979768788 hasConcept C203014093 @default.
• W2979768788 hasConcept C21790070 @default.
• W2979768788 hasConcept C2775934118 @default.
• W2979768788 hasConcept C2778461978 @default.
• W2979768788 hasConcept C2778729363 @default.
• W2979768788 hasConcept C2779282312 @default.
• W2979768788 hasConcept C2780007613 @default.
• W2979768788 hasConcept C2780817109 @default.
• W2979768788 hasConcept C2781187634 @default.
• W2979768788 hasConcept C28328180 @default.
• W2979768788 hasConcept C31573885 @default.
• W2979768788 hasConcept C502942594 @default.
• W2979768788 hasConcept C526805850 @default.
• W2979768788 hasConcept C54355233 @default.
• W2979768788 hasConcept C81885089 @default.
• W2979768788 hasConcept C86803240 @default.
• W2979768788 hasConcept C95444343 @default.
• W2979768788 hasConceptScore W2979768788C109159458 @default.
• W2979768788 hasConceptScore W2979768788C121608353 @default.
• W2979768788 hasConceptScore W2979768788C153911025 @default.
• W2979768788 hasConceptScore W2979768788C190283241 @default.
• W2979768788 hasConceptScore W2979768788C203014093 @default.
• W2979768788 hasConceptScore W2979768788C21790070 @default.
• W2979768788 hasConceptScore W2979768788C2775934118 @default.
• W2979768788 hasConceptScore W2979768788C2778461978 @default.
• W2979768788 hasConceptScore W2979768788C2778729363 @default.
• W2979768788 hasConceptScore W2979768788C2779282312 @default.
• W2979768788 hasConceptScore W2979768788C2780007613 @default.
• W2979768788 hasConceptScore W2979768788C2780817109 @default.
• W2979768788 hasConceptScore W2979768788C2781187634 @default.
• W2979768788 hasConceptScore W2979768788C28328180 @default.
• W2979768788 hasConceptScore W2979768788C31573885 @default.
• W2979768788 hasConceptScore W2979768788C502942594 @default.
• W2979768788 hasConceptScore W2979768788C526805850 @default.
• W2979768788 hasConceptScore W2979768788C54355233 @default.
• W2979768788 hasConceptScore W2979768788C81885089 @default.
• W2979768788 hasConceptScore W2979768788C86803240 @default.
• W2979768788 hasConceptScore W2979768788C95444343 @default.
• W2979768788 hasLocation W29797687881 @default.
• W2979768788 hasOpenAccess W2979768788 @default.
• W2979768788 hasPrimaryLocation W29797687881 @default.
• W2979768788 hasRelatedWork W1530093179 @default.
• W2979768788 hasRelatedWork W1598054001 @default.
• W2979768788 hasRelatedWork W1986152391 @default.
• W2979768788 hasRelatedWork W1988891967 @default.
• W2979768788 hasRelatedWork W2021465890 @default.
• W2979768788 hasRelatedWork W2022894865 @default.
• W2979768788 hasRelatedWork W2092213185 @default.
• W2979768788 hasRelatedWork W2131183720 @default.

• next