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Structural and numerical variation of FLT3/ITD in pediatric AML.

Meshinchi, Soheil and Stirewalt, Derek L and Alonzo, Todd A and Boggon, Titus J and Gerbing, Robert B and Rocnik, Jennifer L and Lange, Beverly J and Gilliland, D Gary and Radich, Jerald P (2008) Structural and numerical variation of FLT3/ITD in pediatric AML. Blood, 111 (10). pp. 4930-4933. ISSN 1528-0020

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Article URL: http://bloodjournal.hematologylibrary.org/cgi/cont...

Abstract

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.

Item Type: Article
Additional Information: Available in PMC: 5/15/09
DOI: 10.1182/blood-2008-01-117770
PubMed ID: 18305215
PMCID: PMC2384125
Keywords or MeSH Headings: 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;
Subjects: Cellular and Organismal Processes > Genetic processes > Mutation
Diseases > Hematologic and lymphatic diseases > Leukemia
Depositing User: Library Staff
Date Deposited: 29 Jan 2009 20:24
Last Modified: 29 Jun 2010 18:51
URI: http://authors.fhcrc.org/id/eprint/241

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