Reference Detail

Ref Type

Journal Article

PMID

(18068628)

Authors

Frohling S, Scholl C, Levine RL, Loriaux M, Boggon TJ, Bernard OA, Berger R, Dohner H, Dohner K, Ebert BL, Teckie S, Golub TR, Jiang J, Schittenhelm MM, Lee BH, Griffin JD, Stone RM, Heinrich MC, Deininger MW, Druker BJ, Gilliland DG

Title

Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer cell	12	6	2007 Dec	501-13	Cancer Cell

URL

Abstract Text

Mutations in the juxtamembrane and kinase domains of FLT3 are common in AML, but it is not known whether alterations outside these regions contribute to leukemogenesis. We used a high-throughput platform to interrogate the entire FLT3 coding sequence in AML patients without known FLT3 mutations and experimentally tested the consequences of each candidate leukemogenic allele. This approach identified gain-of-function mutations that activated downstream signaling and conferred sensitivity to FLT3 inhibition and alleles that were not associated with kinase activation, including mutations in the catalytic domain. These findings support the concept that acquired mutations in cancer may not contribute to malignant transformation and underscore the importance of functional studies to distinguish "driver" mutations underlying tumorigenesis from biologically neutral "passenger" alterations.

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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
FLT3	G831E	missense	unknown	FLT3 G831E lies within the protein kinase domain of the Flt3 protein (UniProt.org). G831E demonstrates autophosphorylation and activation of downstream signaling at similar levels to wild-type Flt3 in culture, but is also predicted to stabilize the autoinhibitory conformation of the Flt3 protein and lead to a loss of function based on structural modeling (PMID: 18068628), and therefore, its effect on Flt3 protein function is unknown.
FLT3	M737I	missense	no effect - predicted	FLT3 M737I lies within the protein kinase domain of the Flt3 protein (UniProt.org). M737I does not result in Il-3 independent growth of cultured cells (PMID: 18068628), and therefore, is predicted to have no effect on Flt3 protein function.
FLT3	R595_L601dup	duplication	gain of function	FLT3 R595_L601dup (also referred to as FLT3 L601_K602insREYEYDL) indicates the insertion of seven duplicate amino acids, arginine (R)-595 through leucine(L)-601, in the juxtamembrane domain of the Flt3 protein (PMID: 11756186). R595_L601dup results in constitutive phosphorylation of Flt3, activation of Stat5 and Erk signaling, transformation of cells in culture, and induction of myeloproliferative disorder in mouse models (PMID: 18068628, PMID: 11756186).
FLT3	R834Q	missense	gain of function	FLT3 R834Q lies within the protein kinase domain of the Flt3 protein (UniProt.org). R834Q results in constitutive phosphorylation of Flt3, activation of Erk signaling, and is transforming in culture (PMID: 18068628).
FLT3	S451F	missense	gain of function	FLT3 S451F lies within the extracellular domain of the Flt3 protein (UniProt.org). S541F results in constitutive phosphorylation of Flt3, activation of Erk signaling, and is transforming in culture (PMID: 18068628).
FLT3	T167A	missense	no effect - predicted	FLT3 T167A lies within the extracellular domain of the Flt3 protein (UniProt.org). T167A does not result in Il-3 independent growth of cultured cells (PMID: 18068628), and therefore, is predicted to have no effect on Flt3 protein function.
FLT3	V194M	missense	no effect - predicted	FLT3 V194M lies within the extracellular domain of the Flt3 protein (UniProt.org). V194M does not result in Il-3 independent growth of cultured cells (PMID: 18068628), and therefore, is predicted to have no effect on Flt3 protein function.
FLT3	V557I	missense	unknown	FLT3 V557I lies within the transmembrane domain of the Flt3 protein (UniProt.org). V557I has been identified in the scientific literature (PMID: 18068628), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Dec 2023).
FLT3	V592G	missense	gain of function	FLT3 V592G lies within a region important for maintaining kinase activity in the Flt3 protein (UniProt.org). V592G results in constitutive phosphorylation of Flt3, activation of Stat3/5, Akt, and Erk signaling, and is transforming in culture (PMID: 18068628).
FLT3	Y364H	missense	no effect - predicted	FLT3 Y364H lies within the extracellular domain of the Flt3 protein (UniProt.org). Y364H does not result in Il-3 independent growth in cultured cells (PMID: 18068628), and therefore, is predicted to have no effect on Flt3 protein function.
FLT3	Y572C	missense	gain of function	FLT3 Y572C lies within the cytoplasmic domain of the Flt3 protein (UniProt.org). Y572C results in constitutive phosphorylation of Flt3, activation of Erk, Akt and Stat signaling, and is transforming in cell culture (PMID: 18068628, PMID: 30651561).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 S451F	Advanced Solid Tumor	decreased response	Midostaurin	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing FLT3 S451F demonstrated decreased sensitivity to inhibition of FLT3 phosphorylation and growth by Rydapt (midostaurin) in culture, when compared to cells expressing other FLT3 activating mutations (PMID: 18068628).	18068628
FLT3 R834Q	Advanced Solid Tumor	sensitive	Midostaurin	Preclinical - Cell culture	Actionable	In a preclinical study, Rydapt (midostaurin) inhibited FLT3-induced phosphorylation of ERK1/2 and reduced growth of transformed cells expressing FLT3 R834Q in culture (PMID: 18068628).	18068628
FLT3 V592G	Advanced Solid Tumor	sensitive	Midostaurin	Preclinical - Cell culture	Actionable	In a preclinical study, Rydapt (midostaurin) inhibited FLT3-induced phosphorylation of ERK1/2 and reduced growth of transformed cells expressing FLT3 V592G in culture (PMID: 18068628).	18068628
FLT3 Y572C	Advanced Solid Tumor	sensitive	Midostaurin	Preclinical - Cell culture	Actionable	In a preclinical study, Rydapt (midostaurin) inhibited FLT3 phosphorylation of ERK1/2 and reduced cell growth in transformed cells expressing FLT3 Y572C in culture (PMID: 18068628).	18068628
FLT3 R834Q	Advanced Solid Tumor	sensitive	PD98059	Preclinical	Actionable	In a preclinical study, PD98059 inhibited ERK1/2 phosphorylation and reduced cell growth in transformed cells expressing FLT3 R834Q (PMID: 18068628).	18068628