FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2979668538> ?p ?o ?g. }

• W2979668538 abstract "Abstract Abstract 3227 PAX5 is a transcription factor expressed in B lymphoid lineage from pro-B cell to mature B cell, and is required for B-cell development and maintenance. De-regulated and reduced PAX5 activity has been implicated in B cell malignancies both in human disease and mouse models. Furthermore, the PAX5 gene is the most frequent target of somatic mutations in childhood and adult B-progenitor acute lymphoblastic leukemia (ALL), being altered in 38.9% and 34% of cases, respectively. These mutations consist of partial or complete hemizygous deletions, homozygous deletions, partial or complete amplifications, point mutations or fusion genes. These aberrations of the PAX5 gene will impair PAX5 function more or less, and will be involved in the block of B-cell differentiation. Chromosomal translocation t(9;15)(p13;q24) was found in 2 cases of childhood ALL and resulted in an in-frame fusion of PAX5 to PML gene. PAX5 moiety of PAX5-PML retains its DNA binding domain but loses its transactivation domain suggesting PAX5-PML will be a dominant negative form of PAX5. PML is originally found as a fusion partner of RARα in PML-RARα, an oncoprotein found in acute promyeloid leukemia (APL), and is now thought to be a tumor suppressor and a pro-apoptotic factor. PML-RARα dominant-negatively affects PML function by disrupting PML nuclear bodies (NBs) where PML exerts its function and gives APL cells survival advantage. These findings give rise a speculation that PAX5-PML not only causes differentiation block by transcriptional repression of PAX5 target genes but also confers a survival advantage by inhibition of PML function. However, no functional analysis has been done for PAX5-PML. Here, we demonstrate that PAX5-PML had a dominant negative effect on both PAX5 and PML. PAX5-PML inhibited transcriptional activity of PAX5 in luciferase reporter assay. PAX5-PML expression also suppressed expression of CD19, one of the transcriptional targets of PAX5, in B-lymphoid cell line. Surprisingly, PAX5-PML hardly showed DNA binding activity in electro mobility shift assay although it retains DNA binding domain of PAX5. Further detailed analyses including, luciferase assay using PAX5-PML with DNA-binding-dead mutations, co-IP assay, and ChIP assay, suggested that transcriptional repression by PAX5-PML was independent of its DNA binding ability, that PAX5 and PAX5-PML formed a heterodimer, and that PAX5-PML bound to CD19 promoter through the association with PAX5 on the promoter. On the other hand, co-expression of PAX5-PML inhibited PML sumoylation, an essential post-translational modification for PML to form NBs, and altered PML localization from NB pattern to diffuse nuclear pattern. Furthermore, treatment with arsenic trioxide, a therapeutic reagent for APL that induces enhancement of PML sumoylation, reconstitution of PML NBs, and apoptosis in APL cells, induced recovery of PML sumoylation and reconstitution of PML NBs also in cells expressing PAX5-PML. More importantly, PAX5-PML expressing HeLa cells showed resistance to PML dependent apoptosis such as apoptosis induced by irradiation and histone deacetylace inhibitor. And arsenic trioxide treatment overcame these apoptosis resistance conferred by PAX5-PML. These data suggest the involvement of this fusion protein in the leukemogenesis of B-ALL in dual-dominant negative manner and the possibility that some cases of ALL can be treated with arsenic trioxide. Disclosures: Hayakawa: Otsuka: Research Funding. Naoe:Chugai: Research Funding; Zenyaku: Research Funding; Kyowa-Kirin: Research Funding; Dainippon-Sumitomo: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Otsuka: Research Funding." @default.
• W2979668538 created "2019-10-18" @default.
• W2979668538 creator A5019005679 @default.
• W2979668538 creator A5027874681 @default.
• W2979668538 creator A5038085877 @default.
• W2979668538 creator A5042332379 @default.
• W2979668538 creator A5069675532 @default.
• W2979668538 creator A5084655190 @default.
• W2979668538 date "2010-11-19" @default.
• W2979668538 modified "2023-10-01" @default.
• W2979668538 title "PAX5-PML Acts as a Dual Dominant-Negative Form of PAX5 and PML" @default.
• W2979668538 doi "https://doi.org/10.1182/blood.v116.21.3227.3227" @default.
• W2979668538 hasPublicationYear "2010" @default.
• W2979668538 type Work @default.
• W2979668538 sameAs 2979668538 @default.
• W2979668538 citedByCount "0" @default.
• W2979668538 crossrefType "journal-article" @default.
• W2979668538 hasAuthorship W2979668538A5019005679 @default.
• W2979668538 hasAuthorship W2979668538A5027874681 @default.
• W2979668538 hasAuthorship W2979668538A5038085877 @default.
• W2979668538 hasAuthorship W2979668538A5042332379 @default.
• W2979668538 hasAuthorship W2979668538A5069675532 @default.
• W2979668538 hasAuthorship W2979668538A5084655190 @default.
• W2979668538 hasConcept C104317684 @default.
• W2979668538 hasConcept C111829193 @default.
• W2979668538 hasConcept C1292079 @default.
• W2979668538 hasConcept C153911025 @default.
• W2979668538 hasConcept C159654299 @default.
• W2979668538 hasConcept C2778453870 @default.
• W2979668538 hasConcept C29447677 @default.
• W2979668538 hasConcept C502942594 @default.
• W2979668538 hasConcept C54355233 @default.
• W2979668538 hasConcept C86339819 @default.
• W2979668538 hasConcept C86803240 @default.
• W2979668538 hasConceptScore W2979668538C104317684 @default.
• W2979668538 hasConceptScore W2979668538C111829193 @default.
• W2979668538 hasConceptScore W2979668538C1292079 @default.
• W2979668538 hasConceptScore W2979668538C153911025 @default.
• W2979668538 hasConceptScore W2979668538C159654299 @default.
• W2979668538 hasConceptScore W2979668538C2778453870 @default.
• W2979668538 hasConceptScore W2979668538C29447677 @default.
• W2979668538 hasConceptScore W2979668538C502942594 @default.
• W2979668538 hasConceptScore W2979668538C54355233 @default.
• W2979668538 hasConceptScore W2979668538C86339819 @default.
• W2979668538 hasConceptScore W2979668538C86803240 @default.
• W2979668538 hasLocation W29796685381 @default.
• W2979668538 hasOpenAccess W2979668538 @default.
• W2979668538 hasPrimaryLocation W29796685381 @default.
• W2979668538 hasRelatedWork W1994554141 @default.
• W2979668538 hasRelatedWork W2007598789 @default.
• W2979668538 hasRelatedWork W2010643205 @default.
• W2979668538 hasRelatedWork W2112938282 @default.
• W2979668538 hasRelatedWork W2138206948 @default.
• W2979668538 hasRelatedWork W2167829546 @default.
• W2979668538 hasRelatedWork W2331403872 @default.
• W2979668538 hasRelatedWork W2344452660 @default.
• W2979668538 hasRelatedWork W2356312197 @default.
• W2979668538 hasRelatedWork W2548707403 @default.
• W2979668538 hasRelatedWork W2550879695 @default.
• W2979668538 hasRelatedWork W2572694230 @default.
• W2979668538 hasRelatedWork W2588082440 @default.
• W2979668538 hasRelatedWork W2589670416 @default.
• W2979668538 hasRelatedWork W2607278499 @default.
• W2979668538 hasRelatedWork W2891325500 @default.
• W2979668538 hasRelatedWork W2897040690 @default.
• W2979668538 hasRelatedWork W3042139394 @default.
• W2979668538 hasRelatedWork W3122379329 @default.
• W2979668538 hasRelatedWork W3139280501 @default.
• W2979668538 isParatext "false" @default.
• W2979668538 isRetracted "false" @default.
• W2979668538 magId "2979668538" @default.
• W2979668538 workType "article" @default.