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Cancer Cell DOI:10.1016/j.ccr.2007.11.005

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

Publication TypeJournal Article
Year of Publication2007
AuthorsFröhling, S, Scholl, C, Levine, RL, Loriaux, M, Boggon, TJ, Bernard, OA, Berger, R, Döhner, H, Döhner, K, Ebert, BL, Teckie, S, Golub, TR, Jiang, J, Schittenhelm, MM, Lee, BH, Griffin, JD, Stone, RM, Heinrich, MC, Deininger, MW, Druker, BJ, D Gilliland, G
JournalCancer Cell
Volume12
Issue6
Pages501-13
Date Published2007 Dec
ISSN1535-6108
KeywordsAdult, Alleles, Animals, Cell Proliferation, DNA Mutational Analysis, Enzyme Activation, fms-Like Tyrosine Kinase 3, Humans, Leukemia, Monocytic, Acute, Mice, Mutant Proteins, Mutation, Phosphorylation, Protein Kinase Inhibitors, Protein Structure, Secondary, Signal Transduction, Staurosporine
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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S1535-6108(07)00336-4
DOI10.1016/j.ccr.2007.11.005
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/18068628?dopt=Abstract

Alternate JournalCancer Cell
PubMed ID18068628
Grant ListCA66996 / CA / NCI NIH HHS / United States
CA113434 / CA / NCI NIH HHS / United States
CA105423 / CA / NCI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
HL082677 / HL / NHLBI NIH HHS / United States