Cancer Cell. 2007 Dec;12(6):501-13.

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

Source

Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

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.

PMID:: 18068628; [PubMed - indexed for MEDLINE]

Publication Types, MeSH Terms, Substances, Grant Support

Publication Types

MeSH Terms

Substances

Grant Support

LinkOut - more resources

Full Text Sources

Other Literature Sources

Supplemental Content

Save items

Related citations in PubMed

Backseat drivers take the wheel. [Cancer Cell. 2007]
Backseat drivers take the wheel.
Futreal PA. Cancer Cell. 2007 Dec; 12(6):493-4.
FMS-like tyrosine kinase 3-internal tandem duplication tyrosine kinase inhibitors display a nonoverlapping profile of resistance mutations in vitro. [Cancer Res. 2009]
FMS-like tyrosine kinase 3-internal tandem duplication tyrosine kinase inhibitors display a nonoverlapping profile of resistance mutations in vitro.
von Bubnoff N, Engh RA, Aberg E, Sänger J, Peschel C, Duyster J. Cancer Res. 2009 Apr 1; 69(7):3032-41. Epub 2009 Mar 24.
Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML. [Blood. 2006]
Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML.
Reindl C, Bagrintseva K, Vempati S, Schnittger S, Ellwart JW, Wenig K, Hopfner KP, Hiddemann W, Spiekermann K. Blood. 2006 May 1; 107(9):3700-7. Epub 2006 Jan 12.
Review Biology, clinical relevance, and molecularly targeted therapy in acute leukemia with FLT3 mutation. [Int J Hematol. 2006]
Review Biology, clinical relevance, and molecularly targeted therapy in acute leukemia with FLT3 mutation.
Kiyoi H, Naoe T. Int J Hematol. 2006 May; 83(4):301-8.
Review Emerging Flt3 kinase inhibitors in the treatment of leukaemia. [Expert Opin Emerg Drugs. 2006]
Review Emerging Flt3 kinase inhibitors in the treatment of leukaemia.
Tickenbrock L, Müller-Tidow C, Berdel WE, Serve H. Expert Opin Emerg Drugs. 2006 Mar; 11(1):153-65.

See reviews... See all...

Cited by 20 PubMed Central articles

Molecular damage in cancer: an argument for mTOR-driven aging. [Aging (Albany NY). 2011]
Molecular damage in cancer: an argument for mTOR-driven aging.
Blagosklonny MV. Aging (Albany NY). 2011 Dec; 3(12):1130-41.
Functional characterization of human cancer-derived TRKB mutations. [PLoS One. 2011]
Functional characterization of human cancer-derived TRKB mutations.
Geiger TR, Song JY, Rosado A, Peeper DS. PLoS One. 2011 Feb 17; 6(2):e16871. Epub 2011 Feb 17.
Protein-tyrosine phosphatase DEP-1 controls receptor tyrosine kinase FLT3 signaling. [J Biol Chem. 2011]
Protein-tyrosine phosphatase DEP-1 controls receptor tyrosine kinase FLT3 signaling.
Arora D, Stopp S, Böhmer SA, Schons J, Godfrey R, Masson K, Razumovskaya E, Rönnstrand L, Tänzer S, Bauer R, et al. J Biol Chem. 2011 Apr 1; 286(13):10918-29. Epub 2011 Jan 24.

See all...

Related information

Related Citations
Calculated set of PubMed citations closely related to the selected article(s) retrieved using a word weight algorithm. Related articles are displayed in ranked order from most to least relevant, with the “linked from” citation displayed first.
Compound (MeSH Keyword)
PubChem chemical compound records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.
Gene
Gene records that cite the current articles. Citations in Gene are added manually by NCBI or imported from outside public resources.
Gene (GeneRIF)
Gene records that have the current articles as Reference into Function citations (GeneRIFs). NLM staff reviewing the literature while indexing MEDLINE add GeneRIFs manually.
HomoloGene
HomoloGene clusters of homologous genes and sequences that cite the current articles. These are references on the Gene and sequence records in the HomoloGene entry.
Nucleotide (RefSeq)
NCBI nucleotide Reference Sequences (RefSeqs) that are cited in the current articles, included in the corresponding Gene Reference into Function, or that include the PubMed articles as references.
Nucleotide (Weighted)
Nucleotide records associated with the current articles through the Gene database. These are the related sequences on the Gene record that are added manually by NCBI.
Protein (RefSeq)
NCBI protein Reference Sequences (RefSeqs) that are cited in the current articles, included in the corresponding Gene Reference into Function, or that include the PubMed articles as references.
Protein (Weighted)
Protein records associated with the current articles through related Gene database records. These are the related sequences on the Gene record that are added manually by NCBI.
Substance (MeSH Keyword)
PubChem chemical substance (submitted) records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.
Taxonomy via GenBank
Taxonomy records associated with the current articles through taxonomic information on related molecular database records (Nucleotide, Protein, Gene, SNP, Structure).
UniGene
UniGene clusters of expressed sequences that are associated with the current articles through references on the clustered sequence records and related Gene records.
GEO Profiles
Gene Expression Omnibus (GEO) Profiles of molecular abundance data. The current articles are references on the Gene record associated with the GEO profile.
Cited in PMC
Full-text articles in the PubMed Central Database that cite the current articles.

Recent activity

Clear Turn Off Turn On

Identification of driver and passenger mutations of FLT3 by high-throughput DNA ...
Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles.
Cancer Cell. 2007 Dec ;12(6):501-13.

PubMed
Mapping the future: organizational, clinical, and research priorities in venous ...
Mapping the future: organizational, clinical, and research priorities in venous disease.
J Vasc Surg. 2007 Dec ;46 Suppl S:84S-93S.

PubMed
Disruption of the ETV6 gene as a consequence of a rare translocation (12;12)(p13...
Disruption of the ETV6 gene as a consequence of a rare translocation (12;12)(p13;q13) in treatment-induced acute myeloid leukemia after breast cancer.
Cancer Genet Cytogenet. 2008 Jan 1 ;180(1):37-42.

PubMed
Health outcomes of bereavement.
Health outcomes of bereavement.
Lancet. 2007 Dec 8 ;370(9603):1960-73.

PubMed
Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipo...
Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies.
Lancet. 2007 Dec 8 ;370(9603):1907-14.

PubMed

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

PubMed

Result Filters

Display Settings:

Send to: