Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles.
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.
Fröhling
Stefan
S
Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Scholl
Claudia
C
Levine
Ross L
RL
Loriaux
Marc
M
Boggon
Titus J
TJ
Bernard
Olivier A
OA
Berger
Roland
R
Döhner
Hartmut
H
Döhner
Konstanze
K
Ebert
Benjamin L
BL
Teckie
Sewit
S
Golub
Todd R
TR
Jiang
Jingrui
J
Schittenhelm
Marcus M
MM
Lee
Benjamin H
BH
Griffin
James D
JD
Stone
Richard M
RM
Heinrich
Michael C
MC
Deininger
Michael W
MW
Druker
Brian J
BJ
Gilliland
D Gary
DG
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*
D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D051941:fms-Like Tyrosine Kinase 3; D019311:Staurosporine; C059539:midostaurin