title: Structural and numerical variation of FLT3/ITD in pediatric AML.
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.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington Medical Center, Seattle, USA. smeshinc@fhcrc.org
authors.forename: Soheil
authors.initials: S
authors.lastname: Meshinchi
authors.forename: Derek L
authors.initials: DL
authors.lastname: Stirewalt
authors.forename: Todd A
authors.initials: TA
authors.lastname: Alonzo
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.forename: Robert B
authors.initials: RB
authors.lastname: Gerbing
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Rocnik
authors.forename: Beverly J
authors.initials: BJ
authors.lastname: Lange
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Jerald P
authors.initials: JP
authors.lastname: Radich
mesh_terms: D000293:Adolescent; D000328:Adult; D001665:Binding Sites; D002648:Child; D002675:Child, Preschool; D018360:Crystallography, X-Ray; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015479:Leukemia, Myelomonocytic, Acute / Q000175:diagnosis / Q000235:genetics*; D011379:Prognosis; D017434:Protein Structure, Tertiary; D050799:STAT5 Transcription Factor; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3 / Q000737:chemistry* / Q000235:genetics*
chemical_list: D050799:STAT5 Transcription Factor; D051941:fms-Like Tyrosine Kinase 3