title: FLT3 K663Q is a novel AML-associated oncogenic kinase: Determination of biochemical properties and sensitivity to Sunitinib (SU11248).
abstract: 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.
authors.affiliation: Department of Pathology and Medicine, Oregon Health and Science University Cancer Institute and Portland Veterans Affairs Medical Center, Portland, OR 97239, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Schittenhelm
authors.forename: K W H
authors.initials: KW
authors.lastname: Yee
authors.forename: J W
authors.initials: JW
authors.lastname: Tyner
authors.forename: L
authors.initials: L
authors.lastname: McGreevey
authors.forename: A D
authors.initials: AD
authors.lastname: Haley
authors.forename: A
authors.initials: A
authors.lastname: Town
authors.forename: D J
authors.initials: DJ
authors.lastname: Griffith
authors.forename: T
authors.initials: T
authors.lastname: Bainbridge
authors.forename: R M
authors.initials: RM
authors.lastname: Braziel
authors.forename: A-M
authors.initials: AM
authors.lastname: O'Farrell
authors.forename: J M
authors.initials: JM
authors.lastname: Cherrington
authors.forename: M C
authors.initials: MC
authors.lastname: Heinrich
mesh_terms: D000208:Acute Disease; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016297:Mutagenesis, Site-Directed; D009368:Neoplasm Transplantation; D017354:Point Mutation; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D000077210:Sunitinib