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

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

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

M M Schittenhelm,K W H Yee,J W Tyner,L McGreevey,A D Haley,A Town,D J Griffith,T Bainbridge,R M Braziel,A-M O'Farrell,J M Cherrington,M C Heinrich,

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.

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

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

For similar enzymes and coenzymes: enzymes: transferases: phosphotransferases: phosphotransferases (alcohol group acceptor): protein kinases: protein-tyrosine kinases: receptor protein-tyrosine kinases: fms-like tyrosine kinase 3 research abstracts see: enzymes and coenzymes: enzymes: transferases: phosphotransferases: phosphotransferases (alcohol group acceptor): protein kinases: protein-tyrosine kinases: receptor protein-tyrosine kinases: fms-like tyrosine kinase 3 research

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

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Leukemia : official journal of the Leukemia Societ

VOLUME: 20

Page Numbers: 2008-14

Journal Abbreviation: Leukemia

ISSN: 0887-6924

DAY: 14

MONTH: 09

YEAR: 2006

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

Number of References:

LANGUAGE: eng

NlmUniqueID: 8704895

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

KEYWORDS: fms-Like Tyrosine Kinase 3

MESH TERMS: metabolism

Chemical & Substance for Abstract: FLT3 K663Q is a novel AML-associated oncogenic kinase: Determination of biochemical properties and sensitivity to Sunitinib (SU11248). Information

Substance Name: FLT3 protein, human

Registry Number: EC 2.7.10.1

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

AFFILIATION: Department of Pathology and Medicine, Oregon Health and Science University Cancer Institute and Portland Veterans Affairs Medical Center, Portland, OR 97239, USA.

Country: England

AGENCY: United States NCI

GRANT: P30 CA69533

ACRONYM: CA

MEDLINETA: Leukemia

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