Reference Detail

Ref Type

Journal Article

PMID

(38049555)

Authors

Gutierrez-Camino A, Richer C, Ouimet M, Fuchs C, Langlois S, Khater F, Caron M, Beaulieu P, St-Onge P, Bataille AR, Sinnett D

Title

Characterisation of FLT3 alterations in childhood acute lymphoblastic leukaemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
British journal of cancer			2023 Dec 04		Br J Cancer

URL

Abstract Text

Alterations of FLT3 are among the most common driver events in acute leukaemia with important clinical implications, since it allows patient classification into prognostic groups and the possibility of personalising therapy thanks to the availability of FLT3 inhibitors. Most of the knowledge on FLT3 implications comes from the study of acute myeloid leukaemia and so far, few studies have been performed in other leukaemias.A comprehensive genomic (DNA-seq in 267 patients) and transcriptomic (RNA-seq in 160 patients) analysis of FLT3 in 342 childhood acute lymphoblastic leukaemia (ALL) patients was performed. Mutations were functionally characterised by in vitro experiments.Point mutations (PM) and internal tandem duplications (ITD) were detected in 4.3% and 2.7% of the patients, respectively. A new activating mutation of the TKD, G846D, conferred oncogenic properties and sorafenib resistance. Moreover, a novel alteration involving the circularisation of read-through transcripts (rt-circRNAs) was observed in 10% of the cases. Patients presenting FLT3 alterations exhibited higher levels of the receptor. In addition, patients with ZNF384- and MLL/KMT2A-rearranged ALL, as well as hyperdiploid subtype, overexpressed FLT3.Our results suggest that specific ALL subgroups may also benefit from a deeper understanding of the biology of FLT3 alterations and their clinical implications.

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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	G846D	missense	gain of function	FLT3 G846D lies within the protein kinase domain of the Flt3 protein (UniProt.org). G846D confers a gain of function to Flt3 as demonstrated by IL3-independent growth and increased Stat5 phosphorylation in cultured cells (PMID: 38049555).
FLT3	Y589D	missense	no effect - predicted	FLT3 Y589D lies within the juxtamembrane domain of the Flt3 protein (PMID: 14759363). Y589D results in Stat5 phosphorylation similar to wild-type Flt3 and does not support IL3-independent growth in cultured cells (PMID: 38049555), and therefore, is predicted to have no effect on Flt3 protein function.

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 G846D	hematologic cancer	sensitive	Midostaurin	Preclinical - Cell culture	Actionable	In a preclinical study, Rydapt (midostaurin) inhibited growth of cells expressing FLT3 G846D in culture (PMID: 38049555).	38049555
FLT3 D835Y	hematologic cancer	sensitive	Midostaurin	Preclinical - Cell culture	Actionable	In a preclinical study, Rydapt (midostaurin) inhibited growth of cells expressing FLT3 D835Y in culture (PMID: 38049555).	38049555
FLT3 G846D	hematologic cancer	resistant	Sorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, a cell line expressing FLT3 G846D was resistant to Nexavar (sorafenib) in culture (PMID: 38049555).	38049555
FLT3 D835Y	hematologic cancer	resistant	Sorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, a cell line expressing FLT3 D835Y was resistant to Nexavar (sorafenib) in culture (PMID: 38049555).	38049555