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

@article{citeulike:2110063, 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.}, address = {Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.}, author = {Fr\"{o}hling, S. and Scholl, C. and Levine, R. L. and Loriaux, M. and Boggon, T. J. and Bernard, O. A. and Berger, R. and D\"{o}hner, H. and D\"{o}hner, K. and Ebert, B. L. and Teckie, S. and Golub, T. R. and Jiang, J. and Schittenhelm, M. M. and Lee, B. H. and Griffin, J. D. and Stone, R. M. and Heinrich, M. C. and Deininger, M. W. and Druker, B. J. and Gilliland, D. G.}, citeulike-article-id = {2110063}, citeulike-linkout-0 = {http://dx.doi.org/10.1016/j.ccr.2007.11.005}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/18068628}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=18068628}, doi = {10.1016/j.ccr.2007.11.005}, issn = {1535-6108}, journal = {Cancer Cell}, keywords = {genetics, medicine, mesophysics, molbio}, month = {December}, number = {6}, pages = {501--513}, posted-at = {2007-12-14 02:30:46}, priority = {2}, title = {Identification of Driver and Passenger Mutations of FLT3 by High-Throughput DNA Sequence Analysis and Functional Assessment of Candidate Alleles.}, url = {http://dx.doi.org/10.1016/j.ccr.2007.11.005}, volume = {12}, year = {2007} }

TY - JOUR ID - citeulike:2110063 L3 - citeulike-article-id:2110063 N2 - 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. IS - 6 JF - Cancer Cell SN - 1535-6108 AD - Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. EP - 513 TI - Identification of Driver and Passenger Mutations of FLT3 by High-Throughput DNA Sequence Analysis and Functional Assessment of Candidate Alleles. VL - 12 SP - 501 KW - genetics KW - medicine KW - mesophysics KW - molbio AU - Fröhling, S AU - Scholl, C AU - Levine, RL AU - Loriaux, M AU - Boggon, TJ AU - Bernard, OA AU - Berger, R AU - Döhner, H AU - Döhner, K AU - Ebert, BL AU - Teckie, S AU - Golub, TR AU - Jiang, J AU - Schittenhelm, MM AU - Lee, BH AU - Griffin, JD AU - Stone, RM AU - Heinrich, MC AU - Deininger, MW AU - Druker, BJ AU - Gilliland, DG PY - 2007/12// UR - http://dx.doi.org/10.1016/j.ccr.2007.11.005 ER -