Structural and numerical variation of FLT3/ITD in pediatric AML.
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.
Meshinchi
Soheil
S
Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington Medical Center, Seattle, USA. smeshinc@fhcrc.org
Stirewalt
Derek L
DL
Alonzo
Todd A
TA
Boggon
Titus J
TJ
Gerbing
Robert B
RB
Rocnik
Jennifer L
JL
Lange
Beverly J
BJ
Gilliland
D Gary
DG
Radich
Jerald P
JP
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*
D050799:STAT5 Transcription Factor; D051941:fms-Like Tyrosine Kinase 3