Publikation
Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles
Wissenschaftlicher Artikel/Review - 01.12.2007
Fröhling Stefan, Jiang Jingrui, Schittenhelm Marcus, Lee Benjamin H, Griffin James D, Stone Richard M, Heinrich Michael C, Deininger Michael W, Druker Brian J, Golub Todd R, Teckie Sewit, Ebert Benjamin L, Scholl Claudia, Levine Ross L, Loriaux Marc, Boggon Titus J, Bernard Olivier A, Berger Roland, Döhner Hartmut, Döhner Konstanze, Gilliland D Gary
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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.