FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2555005241> ?p ?o ?g. }

• W2555005241 abstract "Abstract Abstract 3835 Background: Activation of the RAS pathway plays an important role in the pathogenesis of myeloid malignancies. RAS mutations occur in some 10% of MDS and acute myelogenous leukemia (AML) cases. We previously showed in mouse models of NRASD12/BCL-2 MDS/AML that RAS and BCL-2 co-operate in vivo. These genes co-localize at the plasma membrane in the MDS model (MRP8NRASD12/MMTVLTRTetoBCL-2) with increased apoptosis and in mitochondria in the AML post-MDS model (MRP8[NRASD12/BCL-2] with reduced apoptosis (Omidvar Cancer Res 2007). Here, we screened MDS patients for the cellular co-localizations of RAS:BCL-2 and the consequent apoptosis status. Methods: 39 MDS and AML post-MDS patients were studied, including (WHO classification): 3 RCMD-RS, 3 RCMD, 1 RARS, 8 RAEB I, 9 RAEB II, 4 CMML I, 1 CMML II, 10 AML post-MDS and 2 normal individuals. 17 patients had cytogenetic abnormalities. Bone marrow (BM) mononuclear cells (MNC) were assayed for RAS:BCL-2 localization by confocal and immunofluorescence microscopy. IL-3 dependent mouse hematopoietic FDCP-1 cells were infected with NRASD12 or BCL-2 alone or in combination. Co-localization was measured using anti-NRAS, anti-BCL-2, anti-mitochondrial (Tom 20) and anti-ezrin or anti-wheat germ agglutinin (WGA) plasma membrane antibodies. Apoptosis in patient samples was detected using the Mebstain apoptosis kit and visualized using FITC-dUTP on cytospun cells; apoptosis in the mice was detected by single photon emission computed tomography (SPECT) using technicium labeled annexin-V (99mTc-AnnexinV). NRAS mutations were analyzed by exon direct sequencing or by WAVE, a denaturing high-performance liquid chromatography (DHPLC) based assay. Lineage negative Lin-/Sca-1+/c-Kit+ (LSK) spleen cells were purified by automacs followed by flow sorting. Western blots were probed with anti-caspase 3 and 9 specific antibodies. Results: RAS and BCL-2 were co-expressed in the BM (MNC) of all 39 cases. The intensity (low or high) of RAS:BCL-2 co-localization measured by confocal microscopy significantly correlated with % BM blasts (p=0.0283) and WHO classification (p<0.0001); and was particularly high in 11 of the 12 cases (2 RAEBII, 9 AML post-MDS) with >15% marrow blasts. The intensity of the complex was independent of karyotype and NRAS mutation (found in 3 of 30 (10%) patient samples). The 2 normal samples had low intensities of RAS:BCL-2 co-localizations and wild type NRAS. Further analysis of RAS and BCL-2 co-localizations was carried out in 13 of these patients. In 6 of the 7 patients with BM blasts <15%, more than 10% of cells with apoptotic features (APO+) were seen and the RAS:BCL-2 complex was found at the plasma membrane. On the other hand, 4 of the 6 patients with BM blasts ≥15% showed no apoptotic features (APO-) and a strong co-localization signal of the RAS:BCL-2 complex at the mitochondria. In the remaining 2 patients with BM blasts ≥15% both mitochondria and plasma membrane localization patterns were observed, suggesting a mixed cell population. LSK enriched spleen cells from the AML post-MDS mouse model, and the FDCP-1 cell lines expressing mutant NRAS or BCL-2 alone or in combination were subjected to ligand activated caspase-3 and 9 assays revealed that when BCL-2 is co-localized with NRASD12 at the plasma membrane the anti-apoptotic protective effect of BCL-2 appears to be lost (p<0.0001). This is consistent with the pro-caspase-9-mediated apoptotic features observed in the MDS model determined by Western blotting and further supported by in vivo SPECT apoptosis imaging observed in this model and in low risk MDS patients by FITC-dUTP assays. Conclusion: These findings illustrate the prognostic impact of the intensity of the RAS:BCL-2 complex in MDS/AML post-MDS patients, and further suggest that localization of RAS:BCL-2 at the plasma membrane correlates with less advanced disease while its presence at mitochondria correlates with more advanced MDS. Therapeutic targeting of the RAS:BCL-2 complex could potentially prevent transformation in MDS patients. Disclosures: No relevant conflicts of interest to declare." @default.
• W2555005241 created "2016-11-30" @default.
• W2555005241 creator A5002316165 @default.
• W2555005241 creator A5007605254 @default.
• W2555005241 creator A5008693390 @default.
• W2555005241 creator A5009969425 @default.
• W2555005241 creator A5014838075 @default.
• W2555005241 creator A5015390570 @default.
• W2555005241 creator A5018074362 @default.
• W2555005241 creator A5026162865 @default.
• W2555005241 creator A5042465065 @default.
• W2555005241 creator A5042472345 @default.
• W2555005241 creator A5051624417 @default.
• W2555005241 creator A5051883204 @default.
• W2555005241 creator A5053888516 @default.
• W2555005241 creator A5059057760 @default.
• W2555005241 creator A5075558296 @default.
• W2555005241 creator A5081072676 @default.
• W2555005241 creator A5081849224 @default.
• W2555005241 creator A5083943894 @default.
• W2555005241 creator A5089732539 @default.
• W2555005241 creator A5069676249 @default.
• W2555005241 date "2012-11-16" @default.
• W2555005241 modified "2023-10-18" @default.
• W2555005241 title "NRAS:BCL-2 Complex Localization Determines Anti-Apoptotic Features Associated with Progressive Disease in Myelodysplastic Syndromes (MDS)" @default.
• W2555005241 doi "https://doi.org/10.1182/blood.v120.21.3835.3835" @default.
• W2555005241 hasPublicationYear "2012" @default.
• W2555005241 type Work @default.
• W2555005241 sameAs 2555005241 @default.
• W2555005241 citedByCount "0" @default.
• W2555005241 crossrefType "journal-article" @default.
• W2555005241 hasAuthorship W2555005241A5002316165 @default.
• W2555005241 hasAuthorship W2555005241A5007605254 @default.
• W2555005241 hasAuthorship W2555005241A5008693390 @default.
• W2555005241 hasAuthorship W2555005241A5009969425 @default.
• W2555005241 hasAuthorship W2555005241A5014838075 @default.
• W2555005241 hasAuthorship W2555005241A5015390570 @default.
• W2555005241 hasAuthorship W2555005241A5018074362 @default.
• W2555005241 hasAuthorship W2555005241A5026162865 @default.
• W2555005241 hasAuthorship W2555005241A5042465065 @default.
• W2555005241 hasAuthorship W2555005241A5042472345 @default.
• W2555005241 hasAuthorship W2555005241A5051624417 @default.
• W2555005241 hasAuthorship W2555005241A5051883204 @default.
• W2555005241 hasAuthorship W2555005241A5053888516 @default.
• W2555005241 hasAuthorship W2555005241A5059057760 @default.
• W2555005241 hasAuthorship W2555005241A5069676249 @default.
• W2555005241 hasAuthorship W2555005241A5075558296 @default.
• W2555005241 hasAuthorship W2555005241A5081072676 @default.
• W2555005241 hasAuthorship W2555005241A5081849224 @default.
• W2555005241 hasAuthorship W2555005241A5083943894 @default.
• W2555005241 hasAuthorship W2555005241A5089732539 @default.
• W2555005241 hasConcept C109159458 @default.
• W2555005241 hasConcept C121608353 @default.
• W2555005241 hasConcept C126322002 @default.
• W2555005241 hasConcept C142724271 @default.
• W2555005241 hasConcept C190283241 @default.
• W2555005241 hasConcept C203014093 @default.
• W2555005241 hasConcept C21790070 @default.
• W2555005241 hasConcept C2778461978 @default.
• W2555005241 hasConcept C2779282312 @default.
• W2555005241 hasConcept C2780007613 @default.
• W2555005241 hasConcept C2780817109 @default.
• W2555005241 hasConcept C2781187634 @default.
• W2555005241 hasConcept C28328180 @default.
• W2555005241 hasConcept C502942594 @default.
• W2555005241 hasConcept C526805850 @default.
• W2555005241 hasConcept C55493867 @default.
• W2555005241 hasConcept C71924100 @default.
• W2555005241 hasConcept C86803240 @default.
• W2555005241 hasConcept C95444343 @default.
• W2555005241 hasConceptScore W2555005241C109159458 @default.
• W2555005241 hasConceptScore W2555005241C121608353 @default.
• W2555005241 hasConceptScore W2555005241C126322002 @default.
• W2555005241 hasConceptScore W2555005241C142724271 @default.
• W2555005241 hasConceptScore W2555005241C190283241 @default.
• W2555005241 hasConceptScore W2555005241C203014093 @default.
• W2555005241 hasConceptScore W2555005241C21790070 @default.
• W2555005241 hasConceptScore W2555005241C2778461978 @default.
• W2555005241 hasConceptScore W2555005241C2779282312 @default.
• W2555005241 hasConceptScore W2555005241C2780007613 @default.
• W2555005241 hasConceptScore W2555005241C2780817109 @default.
• W2555005241 hasConceptScore W2555005241C2781187634 @default.
• W2555005241 hasConceptScore W2555005241C28328180 @default.
• W2555005241 hasConceptScore W2555005241C502942594 @default.
• W2555005241 hasConceptScore W2555005241C526805850 @default.
• W2555005241 hasConceptScore W2555005241C55493867 @default.
• W2555005241 hasConceptScore W2555005241C71924100 @default.
• W2555005241 hasConceptScore W2555005241C86803240 @default.
• W2555005241 hasConceptScore W2555005241C95444343 @default.
• W2555005241 hasLocation W25550052411 @default.
• W2555005241 hasOpenAccess W2555005241 @default.
• W2555005241 hasPrimaryLocation W25550052411 @default.
• W2555005241 hasRelatedWork W1598054001 @default.
• W2555005241 hasRelatedWork W1862445054 @default.
• W2555005241 hasRelatedWork W1977873175 @default.
• W2555005241 hasRelatedWork W1993524489 @default.
• W2555005241 hasRelatedWork W2007136279 @default.
• W2555005241 hasRelatedWork W2048045408 @default.
• W2555005241 hasRelatedWork W2353573463 @default.
• W2555005241 hasRelatedWork W2369251668 @default.

• next