Despite therapeutic improvements, a sizable number of T-cell acute lymphoblastic leukemia patients still witness a poor outcome. To unravel the genomic background associated with refractoriness, we evaluated the transcriptome of 19 refractory/early relapsed T-cell acute lymphoblastic leukemia cases (discovery cohort) on diagnostic material by performing RNA-sequencing. The incidence and prognostic impact of the most frequently mutated pathways were validated on diagnostic samples of an independent cohort of 49 cases (validation cohort), including refractory, relapsed and responsive cases, by Sanger sequencing on genomic DNA. Combined gene expression and fusion transcript analyses in the discovery cohort revealed the presence of known oncogenes and identified novel rearrangements inducing overexpression, as well as inactivation of tumor suppressor genes. Mutation analysis identified JAK/STAT and RAS/PTEN as the most commonly disrupted pathways in chemorefractory/early relapsed patients, frequently in association with NOTCH1/FBXW7 mutations. Validation analysis on the validation cohort documented a significantly higher risk of relapse, inferior overall survival, disease-free survival and event-free survival in JAK/STAT and RAS/PTEN altered patients. Conversely, a significantly better survival was observed in patients harboring only NOTCH1/FBXW7 mutations: this favorable prognostic effect was abrogated by the presence of concomitant mutations. Preliminary in vitro assays on primary cells documented sensitivity to specific inhibitors. These data document the negative prognostic impact of JAK/STAT and RAS/PTEN mutations in T-cell acute lymphoblastic leukemia and suggest the potential clinical application of JAK and PI3K/mTOR inhibitors in patients harboring mutations in these pathways.
RNAseq unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications
GAIDANO, Gianluca;
2016-01-01
Abstract
Despite therapeutic improvements, a sizable number of T-cell acute lymphoblastic leukemia patients still witness a poor outcome. To unravel the genomic background associated with refractoriness, we evaluated the transcriptome of 19 refractory/early relapsed T-cell acute lymphoblastic leukemia cases (discovery cohort) on diagnostic material by performing RNA-sequencing. The incidence and prognostic impact of the most frequently mutated pathways were validated on diagnostic samples of an independent cohort of 49 cases (validation cohort), including refractory, relapsed and responsive cases, by Sanger sequencing on genomic DNA. Combined gene expression and fusion transcript analyses in the discovery cohort revealed the presence of known oncogenes and identified novel rearrangements inducing overexpression, as well as inactivation of tumor suppressor genes. Mutation analysis identified JAK/STAT and RAS/PTEN as the most commonly disrupted pathways in chemorefractory/early relapsed patients, frequently in association with NOTCH1/FBXW7 mutations. Validation analysis on the validation cohort documented a significantly higher risk of relapse, inferior overall survival, disease-free survival and event-free survival in JAK/STAT and RAS/PTEN altered patients. Conversely, a significantly better survival was observed in patients harboring only NOTCH1/FBXW7 mutations: this favorable prognostic effect was abrogated by the presence of concomitant mutations. Preliminary in vitro assays on primary cells documented sensitivity to specific inhibitors. These data document the negative prognostic impact of JAK/STAT and RAS/PTEN mutations in T-cell acute lymphoblastic leukemia and suggest the potential clinical application of JAK and PI3K/mTOR inhibitors in patients harboring mutations in these pathways.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
