Publication Type | Journal Article |
Year of Publication | 2007 |
Authors | Fröhling, 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 |
Journal | Cancer Cell |
Volume | 12 |
Issue | 6 |
Pages | 501-13 |
Date Published | 2007 Dec |
ISSN | 1535-6108 |
Keywords | Adult, 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. |
URL | http://linkinghub.elsevier.com/retrieve/pii/S1535-6108(07)00336-4 |
DOI | 10.1016/j.ccr.2007.11.005 |
Pubmed | |
Alternate Journal | Cancer Cell |
PubMed ID | 18068628 |
Grant List | CA66996 / 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 |
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.
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