{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["4"],"submitter":["Chougule RA"],"pubmed_abstract":["The response of childhood acute lymphoblastic leukemia (ALL) to dexamethasone predicts the long-term remission outcome. To explore the mechanisms of dexamethasone resistance in B cell ALL (B-ALL), we generated dexamethasone-resistant clones by prolonged treatment with dexamethasone. Using RNA-sequencing and high-throughput screening, we found that dexamethasone-resistant cells are dependent on receptor tyrosine kinases. Further analysis with phosphokinase arrays showed that the type III receptor tyrosine kinase FLT3 is constitutively active in resistant cells. Targeted next-generation and Sanger sequencing identified an internal tandem duplication mutation and a point mutation (R845G) in FLT3 in dexamethasone-resistant cells, which were not present in the corresponding sensitive clones. Finally, we showed that resistant cells displayed sensitivity to second-generation FLT3 inhibitors both in vitro and in vivo. Collectively, our data suggest that long-term dexamethasone treatment selects cells with a distinct genetic background, in this case oncogenic FLT3, and therefore therapies targeting FLT3 might be useful for the treatment of relapsed B-ALL patients."],"journal":["NPJ genomic medicine"],"pagination":["7"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6449402"],"repository":["biostudies-literature"],"pubmed_title":["Glucocorticoid-resistant B cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation."],"pmcid":["PMC6449402"],"pubmed_authors":["Chougule RA","Kazi JU","Vallon-Christersson J","Shah K","Moharram SA"],"additional_accession":[]},"is_claimable":false,"name":"Glucocorticoid-resistant B cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation.","description":"The response of childhood acute lymphoblastic leukemia (ALL) to dexamethasone predicts the long-term remission outcome. To explore the mechanisms of dexamethasone resistance in B cell ALL (B-ALL), we generated dexamethasone-resistant clones by prolonged treatment with dexamethasone. Using RNA-sequencing and high-throughput screening, we found that dexamethasone-resistant cells are dependent on receptor tyrosine kinases. Further analysis with phosphokinase arrays showed that the type III receptor tyrosine kinase FLT3 is constitutively active in resistant cells. Targeted next-generation and Sanger sequencing identified an internal tandem duplication mutation and a point mutation (R845G) in FLT3 in dexamethasone-resistant cells, which were not present in the corresponding sensitive clones. Finally, we showed that resistant cells displayed sensitivity to second-generation FLT3 inhibitors both in vitro and in vivo. Collectively, our data suggest that long-term dexamethasone treatment selects cells with a distinct genetic background, in this case oncogenic FLT3, and therefore therapies targeting FLT3 might be useful for the treatment of relapsed B-ALL patients.","dates":{"release":"2019-01-01T00:00:00Z","publication":"2019","modification":"2024-11-06T03:14:12.253Z","creation":"2019-06-05T16:17:28Z"},"accession":"S-EPMC6449402","cross_references":{"pubmed":["30962949"],"doi":["10.1038/s41525-019-0082-y"]}}