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 Cancer cell
Vol 12
Issue 6
Date 2007 Dec
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 Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
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.
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 in one study (PMID: 18068628) and therefore, is predicted to have no effect on Flt3 protein function.
R595_L601dup duplication gain of function FLT3 R595_L601dup (also referred to as FLT3 L601_K602insREYEYDL) indicates the insertion of 7 duplicate amino acids, arginine (R)-595 through leucine(L)-601, in the juxtamembrane region 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).
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).
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).
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 in one study (PMID: 18068628) and therefore, is predicted to have no effect on Flt3 protein function.
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 in one study (PMID: 18068628) and therefore, is predicted to have no effect on Flt3 protein function.
V557I missense unknown FLT3 V557I lies within the transmembrane domain of the Flt3 protein (PMID: 18068628). 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, Oct 2018).
V592G missense gain of function FLT3 V592G lies within the protein kinase domain of 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).
Y364H missense no effect - predicted FLT3 Y364H lies within the extracellular domain of the Flt3 protein (PMID: 18068628). Y364H does not result in IL-3 independent growth of cultured cells in one study (PMID: 18068628) and therefore, is predicted to have no effect on Flt3 protein function.
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).
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 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
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 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