@article{1c2f58c8489a473eaf9717c423a3a4fc,
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.",
keywords = "CELLCYCLE",
author = "Stefan Fr{\"o}hling and Claudia Scholl and Levine, {Ross L.} and Marc Loriaux and Boggon, {Titus J.} and Bernard, {Olivier A.} and Roland Berger and Hartmut D{\"o}hner and Konstanze D{\"o}hner and Ebert, {Benjamin L.} and Sewit Teckie and Golub, {Todd R.} and Jingrui Jiang and Schittenhelm, {Marcus M.} and Lee, {Benjamin H.} and Griffin, {James D.} and Stone, {Richard M.} and Heinrich, {Michael C.} and Deininger, {Michael W.} and Druker, {Brian J.} and Gilliland, {D. Gary}",
note = "Funding Information: We are grateful to Maricel Gozo for technical support and to Jeffrey C. Lee, Matthew Meyerson, J. Guillermo P{\'a}ez, and William R. Sellers for assistance with the kinase sequencing platform. This work was supported by National Institutes of Health grants HL082677 (to R.L.L.), CA113434 (to B.H.L.), CA66996 (to D.G.G.), and CA105423 (to D.G.G.), a Veterans Affairs Merit Review Grant (to M.C.H.), and grants from the Doris Duke Charitable Foundation (to M.C.H., B.J.D., and D.G.G.) and the Leukemia and Lymphoma Society (to B.J.D. and D.G.G.). S.F. and C.S. are supported by grants from the Deutsche Forschungsgemeinschaft. R.L.L. is the recipient of an American Society of Hematology Basic Research Fellow Award, an American Society of Clinical Oncology Young Investigator Award, and a Doris Duke Charitable Foundation Clinical Development Scientist Award. T.J.B. is the recipient of an American Society of Hematology Junior Faculty Scholar Award. M.M.S. is supported by grants from the Deutsche Krebshilfe and the Fort{\"u}ne Program of the University of T{\"u}bingen. D.G.G. is a Doris Duke Charitable Foundation Distinguished Clinical Scientist. M.C.H. and B.J.D. are scientific founders of MolecularMD, a company that specializes in the development of molecular assays for leukemias, lymphomas, and solid tumors. All other authors declare that they have no competing financial interests. ",
year = "2007",
month = dec,
day = "6",
doi = "10.1016/j.ccr.2007.11.005",
language = "English",
volume = "12",
pages = "501--513",
journal = "Cancer Cell",
issn = "1535-6108",
number = "6",
}