Glucocorticoid-resistant B cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation

Research output: Contribution to journalArticle


title = "Glucocorticoid-resistant B cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation",
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.",
author = "Chougule, {Rohit A.} and Kinjal Shah and Moharram, {Sausan A.} and Johan Vallon-Christersson and Kazi, {Julhash U.}",
year = "2019",
month = "4",
day = "4",
doi = "10.1038/s41525-019-0082-y",
language = "English",
volume = "4",
journal = "npj Genomic Medicine",
issn = "2056-7944",
publisher = "Nature Publishing Group",
number = "1",