FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2738594396> ?p ?o ?g. }

• W2738594396 endingPage "4068" @default.
• W2738594396 startingPage "4068" @default.
• W2738594396 abstract "Abstract Acute Lymphoblastic Leukemia (ALL) is the most common malignancy in children. Altogether 90% of pediatric ALL patients achieve a complete hematologic remission with current high dose combination chemotherapy and 80% of them remain leukemia free. However, the outcome for patients showing refractory disease or those whose leukemia relapses after an initial transient response remains disappointingly poor with cure rates of less than 40%. To investigate genetic drivers of relapse and resistance and explore the specific roles of clonal evolution in disease progression and relapse here we performed whole-exome sequence analysis of matched diagnosis, germline (remission) and relapse DNA samples in a panel of 55 pediatric ALL patients including 33 T-cell ALLs and 22 B-cell precursor ALLs. These analyses identified an average of 9 mutations present in diagnostic samples and 17 mutations in relapsed leukemia DNAs. Phylogenetic tree analysis for each of the 48 cases with optimal variant call parameters analyzing their clonal evolution dynamics during disease progression, combined with whole genome sequencing of targeted samples with low exonic mutation input, showed that branched evolution in which relapse clones contain some, but not all genetic lesions present in the major clone at diagnosis as the primary mechanism driving tumor progression and relapse present in 45/48 (94%) cases. In addition, and consistent with previous reports we identified the presence of chemotherapy associated mutations in NT5C2 (10/55), TP53 (3/55), CREBBP (4/55) and the NR3C1 glucocorticoid receptor gene (2/55). However, and most strikingly, 23/27 (85%) recurrently mutated genes in this series with mutations preferentially selected or retained at the time of relapse (mutation never lost in the relapse clone) were not implicated in relapse ALL before (HTR3A, MED12, USP9X, CACNA1H, ODZ3, AACS, SAMD4A, ANO5, PAPPA, NAALADL2, HIST3H2A, FZD7, TBX15, NEB, GREB1L, PLXNA4, SGK223, TSC1, PTPRG, FGF10, SYCP2, TRPM3 and EYS). A branched pattern of genetic evolution and the presence of recurrent mutations selected at relapse support that chemotherapy imposes a strong Darwinian genetic selection in leukemic cell populations. In this context it is worth noting that RAS-MAPK pathway activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series. Interestingly, some leukemias showed retention or emergence of RAS mutant clones at relapse, while in others, RAS mutant clones present at diagnosis were replaced by RAS wild type populations, supporting a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia. Most notably, and in agreement with this hypothesis, inducible expression of mutant KRAS in human ALL lines demonstrate that oncogenic KRAS G12D induces methotrexate resistance, but also improves leukemia response to vincristine; a phenotype perfectly recapitulated in a isogenic ALL leukemia model generated from a conditional inducible Kras G12D knockin mice. Mechanistically, KRAS G12 expression induces MAPK dependent abrogation of methotrexate induced apoptosis. Moreover, Kras mutant tumors show enhanced G2/M cell cycle arrest and apoptosis upon spindle poisoning with vincristine, a phenotype linked with increased PLK phosphorylation and transcriptional down-regulation of mitotic genes. Finally clonal competition assays demonstrate that the differential response to methotrexate and vincristine in isogenic Kras wild type and Kras mutant ALL cells results in clonal dominance of Kras G12D populations in cultures treated with methotrexate, while Kras wild type cells are selected the context of vincristine treatment. In all these results show novel insight on the genetics and mechanisms of clonal selection, disease progression and relapse in ALL and demonstrate a previously unrecognized dual role of RAS mutations in chemotherapy response. Disclosures Loh: Abbvie: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees." @default.
• W2738594396 created "2017-07-31" @default.
• W2738594396 creator A5002649650 @default.
• W2738594396 creator A5004844905 @default.
• W2738594396 creator A5006908499 @default.
• W2738594396 creator A5009656123 @default.
• W2738594396 creator A5010840699 @default.
• W2738594396 creator A5017811469 @default.
• W2738594396 creator A5018323469 @default.
• W2738594396 creator A5018962418 @default.
• W2738594396 creator A5019526444 @default.
• W2738594396 creator A5020549289 @default.
• W2738594396 creator A5028411277 @default.
• W2738594396 creator A5029718580 @default.
• W2738594396 creator A5035631836 @default.
• W2738594396 creator A5046980140 @default.
• W2738594396 creator A5048997408 @default.
• W2738594396 creator A5051981929 @default.
• W2738594396 creator A5054113987 @default.
• W2738594396 creator A5056128255 @default.
• W2738594396 creator A5060274149 @default.
• W2738594396 creator A5068279591 @default.
• W2738594396 creator A5071265000 @default.
• W2738594396 creator A5075983414 @default.
• W2738594396 creator A5078387402 @default.
• W2738594396 creator A5085010022 @default.
• W2738594396 creator A5087836251 @default.
• W2738594396 date "2016-12-02" @default.
• W2738594396 modified "2023-10-16" @default.
• W2738594396 title "Mutational Landscape, Clonal Evolution Patterns and Role of RAS Mutations in Relapsed Acute Lymphoblastic Leukemia" @default.
• W2738594396 doi "https://doi.org/10.1182/blood.v128.22.4068.4068" @default.
• W2738594396 hasPublicationYear "2016" @default.
• W2738594396 type Work @default.
• W2738594396 sameAs 2738594396 @default.
• W2738594396 citedByCount "0" @default.
• W2738594396 crossrefType "journal-article" @default.
• W2738594396 hasAuthorship W2738594396A5002649650 @default.
• W2738594396 hasAuthorship W2738594396A5004844905 @default.
• W2738594396 hasAuthorship W2738594396A5006908499 @default.
• W2738594396 hasAuthorship W2738594396A5009656123 @default.
• W2738594396 hasAuthorship W2738594396A5010840699 @default.
• W2738594396 hasAuthorship W2738594396A5017811469 @default.
• W2738594396 hasAuthorship W2738594396A5018323469 @default.
• W2738594396 hasAuthorship W2738594396A5018962418 @default.
• W2738594396 hasAuthorship W2738594396A5019526444 @default.
• W2738594396 hasAuthorship W2738594396A5020549289 @default.
• W2738594396 hasAuthorship W2738594396A5028411277 @default.
• W2738594396 hasAuthorship W2738594396A5029718580 @default.
• W2738594396 hasAuthorship W2738594396A5035631836 @default.
• W2738594396 hasAuthorship W2738594396A5046980140 @default.
• W2738594396 hasAuthorship W2738594396A5048997408 @default.
• W2738594396 hasAuthorship W2738594396A5051981929 @default.
• W2738594396 hasAuthorship W2738594396A5054113987 @default.
• W2738594396 hasAuthorship W2738594396A5056128255 @default.
• W2738594396 hasAuthorship W2738594396A5060274149 @default.
• W2738594396 hasAuthorship W2738594396A5068279591 @default.
• W2738594396 hasAuthorship W2738594396A5071265000 @default.
• W2738594396 hasAuthorship W2738594396A5075983414 @default.
• W2738594396 hasAuthorship W2738594396A5078387402 @default.
• W2738594396 hasAuthorship W2738594396A5085010022 @default.
• W2738594396 hasAuthorship W2738594396A5087836251 @default.
• W2738594396 hasConcept C104317684 @default.
• W2738594396 hasConcept C10590036 @default.
• W2738594396 hasConcept C113968399 @default.
• W2738594396 hasConcept C143998085 @default.
• W2738594396 hasConcept C16671776 @default.
• W2738594396 hasConcept C2778461978 @default.
• W2738594396 hasConcept C2779399171 @default.
• W2738594396 hasConcept C2781107101 @default.
• W2738594396 hasConcept C2909962599 @default.
• W2738594396 hasConcept C501734568 @default.
• W2738594396 hasConcept C502942594 @default.
• W2738594396 hasConcept C54355233 @default.
• W2738594396 hasConcept C71924100 @default.
• W2738594396 hasConcept C81089528 @default.
• W2738594396 hasConcept C86803240 @default.
• W2738594396 hasConceptScore W2738594396C104317684 @default.
• W2738594396 hasConceptScore W2738594396C10590036 @default.
• W2738594396 hasConceptScore W2738594396C113968399 @default.
• W2738594396 hasConceptScore W2738594396C143998085 @default.
• W2738594396 hasConceptScore W2738594396C16671776 @default.
• W2738594396 hasConceptScore W2738594396C2778461978 @default.
• W2738594396 hasConceptScore W2738594396C2779399171 @default.
• W2738594396 hasConceptScore W2738594396C2781107101 @default.
• W2738594396 hasConceptScore W2738594396C2909962599 @default.
• W2738594396 hasConceptScore W2738594396C501734568 @default.
• W2738594396 hasConceptScore W2738594396C502942594 @default.
• W2738594396 hasConceptScore W2738594396C54355233 @default.
• W2738594396 hasConceptScore W2738594396C71924100 @default.
• W2738594396 hasConceptScore W2738594396C81089528 @default.
• W2738594396 hasConceptScore W2738594396C86803240 @default.
• W2738594396 hasIssue "22" @default.
• W2738594396 hasLocation W27385943961 @default.
• W2738594396 hasOpenAccess W2738594396 @default.
• W2738594396 hasPrimaryLocation W27385943961 @default.
• W2738594396 hasRelatedWork W1978707316 @default.
• W2738594396 hasRelatedWork W2013355657 @default.
• W2738594396 hasRelatedWork W2024354035 @default.

• next