Document Detail


Structural and numerical variation of FLT3/ITD in pediatric AML.
MedLine Citation:
PMID:  18305215     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
FLT3 internal tandem duplication (FLT3/ITD) is a common somatic mutation in acute myeloid leukemia (AML) with significant variation in the position, length, and number of duplications of the FLT3 gene. We evaluated these physical characteristics in FLT3/ITD-positive patients who were treated on CCG-2941/2961 and correlated them with clinical outcome. Fiftynine of 77 FLT3/ITD-positive patients (77%) had a single ITD, 16 (21%) had 2 ITDs, and 2 (3%) had 3 ITDs. The length of the duplicated region varied from 6 to 51 amino acids, and in all cases amino acid residues Y591-Y597 were duplicated. Structural analysis demonstrated that Y591-Y597 encodes the switch and zipper regions of the juxtamembrane domain of FLT3. In addition, 24 of 77 patients (31%) had duplication of the critical STAT5 docking sites Y589/591. Patients with longer ITDs had a worse relapse-free survival (19% vs 51%, P = .035), while the presence of more than 1 ITD was not clinically significant. Physical characteristics including the length of FLT3/ITD may influence FLT3 activation state by altering its structure and may impact response to therapy.
Authors:
Soheil Meshinchi; Derek L Stirewalt; Todd A Alonzo; Titus J Boggon; Robert B Gerbing; Jennifer L Rocnik; Beverly J Lange; D Gary Gilliland; Jerald P Radich
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-02-27
Journal Detail:
Title:  Blood     Volume:  111     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2008 May 
Date Detail:
Created Date:  2008-05-09     Completed Date:  2008-07-10     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4930-3     Citation Subset:  AIM; IM    
Affiliation:
Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington Medical Center, Seattle, USA. smeshinc@fhcrc.org
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Binding Sites
Child
Child, Preschool
Crystallography, X-Ray
DNA Mutational Analysis
Disease-Free Survival
Humans
Infant
Infant, Newborn
Leukemia, Myelomonocytic, Acute / diagnosis,  genetics*
Prognosis
Protein Structure, Tertiary
STAT5 Transcription Factor
Tandem Repeat Sequences*
fms-Like Tyrosine Kinase 3 / chemistry*,  genetics*
Grant Support
ID/Acronym/Agency:
CA114563/CA/NCI NIH HHS; CA18029/CA/NCI NIH HHS; CA32102/CA/NCI NIH HHS; K23 CA92405/CA/NCI NIH HHS; R01 CA114563/CA/NCI NIH HHS; R21 CA102624/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/STAT5 Transcription Factor; EC 2.7.10.1/fms-Like Tyrosine Kinase 3
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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