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|Ref Type||Journal Article|
|Authors||Chougule RA, Shah K, Moharram SA, Vallon-Christersson J, Kazi JU|
|Title||Glucocorticoid-resistant B cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation.|
|Journal||NPJ genomic medicine|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|FLT3||R845G||missense||unknown||FLT3 R845G lies within the activation loop of the protein kinase domain of the Flt3 protein (PMID: 25837374). R845G has been demonstrated to occur as a secondary resistance mutation in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 25847190, PMID: 30962949), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Oct 2022).||Y|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|FLT3 E598_Y599insFDFREYE FLT3 R845G||B-cell adult acute lymphocytic leukemia||sensitive||Crenolanib||Preclinical - Cell culture||Actionable||In a preclinical study, B-cell acute lymphocytic leukemia cells harboring FLT3 R845G and FLT3 E598_Y599insFDFREYE were sensitive to treatment with Crenolanib, demonstrating decreased cell viability in culture (PMID: 30962949).||30962949|
|FLT3 E598_Y599insFDFREYE FLT3 R845G||B-cell adult acute lymphocytic leukemia||sensitive||Quizartinib||Preclinical - Cell culture||Actionable||In a preclinical study, B-cell acute lymphocytic leukemia cells harboring FLT3 R845G and FLT3 E598_Y599insFDFREYE were sensitive to treatment with Vanflyta (quizartinib), demonstrating decreased cell viability in culture (PMID: 30962949).||30962949|