title: Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles.
abstract: 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.
authors: Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Stefan
authors: S
authors: Fröhling
authors: Claudia
authors: C
authors: Scholl
authors: Ross L
authors: RL
authors: Levine
authors: Marc
authors: M
authors: Loriaux
authors: Titus J
authors: TJ
authors: Boggon
authors: Olivier A
authors: OA
authors: Bernard
authors: Roland
authors: R
authors: Berger
authors: Hartmut
authors: H
authors: Döhner
authors: Konstanze
authors: K
authors: Döhner
authors: Benjamin L
authors: BL
authors: Ebert
authors: Sewit
authors: S
authors: Teckie
authors: Todd R
authors: TR
authors: Golub
authors: Jingrui
authors: J
authors: Jiang
authors: Marcus M
authors: MM
authors: Schittenhelm
authors: Benjamin H
authors: BH
authors: Lee
authors: James D
authors: JD
authors: Griffin
authors: Richard M
authors: RM
authors: Stone
authors: Michael C
authors: MC
authors: Heinrich
authors: Michael W
authors: MW
authors: Deininger
authors: Brian J
authors: BJ
authors: Druker
authors: D Gary
authors: DG
authors: Gilliland
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004252:DNA Mutational Analysis; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007948:Leukemia, Monocytic, Acute / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017433:Protein Structure, Secondary; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000737:chemistry / Q000235:genetics*
chemical_list: D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D051941:fms-Like Tyrosine Kinase 3; D019311:Staurosporine; C059539:midostaurin