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Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles.

Cancer cell | 2007

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.

Pubmed ID: 18068628 RIS Download

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Associated grants

  • Agency: NCI NIH HHS, United States
    Id: CA66996
  • Agency: NCI NIH HHS, United States
    Id: CA113434
  • Agency: NCI NIH HHS, United States
    Id: CA105423
  • Agency: NCI NIH HHS, United States
    Id: T32 CA009172
  • Agency: NHLBI NIH HHS, United States
    Id: HL082677

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Mutation Surveyor (tool)

RRID:SCR_001247

THIS RESOURCE IS NO LONGER IN SERVICE. Documented on September 23,2022. Software for DNA sequencing analysis that integates with Sanger Sequencing files generated by Applied Biosystems Genetic Analyzers, MegaBACE, and Beckman CEQ electrophoresis systems. It can be used to find single nucleotide polymorphisms (SNPs), insertions and deletions (INDELS), and somatic mutations in direct sequencing, PCR sequencing, mitochondrial DNA sequencing, and resequencing projects.

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