Reference Detail

Ref Type

Journal Article

PMID

(16990784)

Authors

Schittenhelm MM, Yee KW, Tyner JW, McGreevey L, Haley AD, Town A, Griffith DJ, Bainbridge T, Braziel RM, O'Farrell AM, Cherrington JM, Heinrich MC

Title

FLT3 K663Q is a novel AML-associated oncogenic kinase: Determination of biochemical properties and sensitivity to Sunitinib (SU11248).

Journal	Vol	Issue	Date	Pages	Journal Short Title
Leukemia	20	11	2006 Nov	2008-14	Leukemia

URL

Abstract Text

Somatic mutations of FLT3 resulting in constitutive kinase activation are the most common acquired genomic abnormality found in acute myeloid leukemia (AML). The majority of these mutations are internal tandem duplications (ITD) of the juxtamembrane region (JM). In addition, a minority of cases of AML are associated with mutation of the FLT3 activation loop (AL), typically involving codons D835 and/or I836. We hypothesized that other novel mutations of FLT3 could also contribute to leukemogenesis. We genotyped 109 cases of AML and identified two novel gain-of-function mutations. The first mutation, N841 H, is similar to previously described mutations involving amino-acid substitutions of codon 841. The other novel mutation, FLT3 K663Q, is the first AML-associated gain-of-function mutation located outside the JM and AL domains. Of note, this mutation was potently inhibited by Sunitinib (SU11248), a previously described FLT3 kinase inhibitor. Sunitinib reduced the proliferation and induced apoptosis of transformed Ba/F3 cells expressing FLT3 K663Q. The potency of Sunitinib against FLT3 K663Q was similar to its potency against FLT3 ITD mutations. We conclude that FLT3 mutations in AML can involve novel regions of the TK1. Future studies are needed to define the incidence and prognostic significance of FLT3 mutations outside the well-established JM and AL regions.

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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	K663Q	missense	gain of function - predicted	FLT3 K663Q lies within the protein kinase domain of the Flt3 protein (UniProt.org). K663Q results in constitutive phosphorylation of Flt3 and activation of Akt, Mapk, and Stat pathways in cell culture (PMID: 16990784), and therefore, is predicted to lead to a gain of Flt3 protein function.
FLT3	N841H	missense	unknown	FLT3 N841H lies within the protein kinase domain of the Flt3 protein (UniProt.org). N841H has been identified in the scientific literature (PMID: 32040554, PMID: 24623852, PMID: 16990784), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Sep 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 K663Q	hematologic cancer	sensitive	Sunitinib	Preclinical - Cell culture	Actionable	In a preclinical study, Sutent (sunitinib) resulted in inhibition of cell proliferation, reduced phosphorylation of Flt3, Akt, Mapk, and Stat5, and induced apoptosis in transformed cells expressing FLT3 K663Q in culture (PMID: 16990784).	16990784