Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
NPJ genomic medicine	4		2019	7	NPJ Genom Med

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, May 2024).	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