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Ref Type Journal Article
PMID (30962949)
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
Vol 4
Issue
Date 2019
URL
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.

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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, Sep 2021). 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 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
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