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PMID: 18305215 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Blood ·Vol. 111 ·No. 10 ·2008-05-15 ·Pages 4930-3

Meshinchi S, Stirewalt DL, Alonzo TA, Boggon TJ, Gerbing RB, Rocnik JL, Lange BJ, Gilliland DG, Radich JP

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.

MeSH Terms
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
Chemicals
STAT5 Transcription Factor fms-Like Tyrosine Kinase 3
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Meshinchi Soheil
Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington Medical Center, Seattle, USA. smeshinc@fhcrc.org
Stirewalt Derek L
Alonzo Todd A
Boggon Titus J
Gerbing Robert B
Rocnik Jennifer L
Lange Beverly J
Gilliland D Gary
Radich Jerald P
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
1528-0020
DOI
10.1182/blood-2008-01-117770
Email
smeshinc@fhcrc.org
Published
2008-05-15
Epub
2008-00-27
Pages
4930-3
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC2384125
Subset
IM
Grants
NCI NIH HHS · CA18029 · United States
NCI NIH HHS · K23 CA092405 · United States
NCI NIH HHS · R01 CA114563 · United States
NCI NIH HHS · R21 CA102624 · United States
NCI NIH HHS · K23 CA92405 · United States
NCI NIH HHS · P01 CA018029 · United States
NCI NIH HHS · N01 CA032102 · United States
NCI NIH HHS · CA114563 · United States
NCI NIH HHS · U10 CA032102 · United States
External Links
PubMed source DOI: 10.1182/blood-2008-01-117770 PMC Full Text View journal details
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