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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.
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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 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 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 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
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