Identification of Driver and Passenger Mutations of FLT3 by High-Throughput DNA Sequence Analysis and Functional Assessment of Candidate Alleles

Stefan Fröhling, Claudia Scholl, Ross L. Levine, Marc Loriaux, Titus J. Boggon, Olivier A. Bernard, Roland Berger, Hartmut Döhner, Konstanze Döhner, Benjamin L. Ebert, Sewit Teckie, Todd R. Golub, Jingrui Jiang, Marcus M. Schittenhelm, Benjamin H. Lee, James D. Griffin, Richard M. Stone, Michael C. Heinrich, Michael W. Deininger, Brian J. DrukerD. Gary Gilliland

Research output: Contribution to journalArticle

134 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)501-513
Number of pages13
JournalCancer Cell
Volume12
Issue number6
DOIs
StatePublished - Dec 6 2007

Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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