Submitted January 8, 2008
Accepted February 24, 2008
Structural and numerical variation of FLT3/ITD in pediatric AML
Soheil Meshinchi*, Derek L Stirewalt, Todd A Alonzo, Titus J Boggon, Robert B Gerbing, Jennifer L. Rocnik, Beverly J. Lange, D Gary Gilliland, and Jerald P. Radich
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Department of Medicine, University of Washington Medical Center, Seattle, WA
Department of Statistics, University of Southern California Keck School of Medicine, Los Angeles, CA
Department of Pharmacology, Yale University Medical School, New Haven, CT
Childrens Oncology Group, Arcadia, CA
Division of Hematology/Oncology, Department of Pathology, Brigham and Women's Hopsital and the Howard Hughes Medical Institute, Harvard Medical School, Boston, MA
* Corresponding author; email: smeshinc{at}fhcrc.org.
FLT3/ITD is a common somatic mutation in 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. 59/77 FLT3/ITD-positive patients (77%) had a single ITD, 16 (21%) had two ITDs, and 2 (3%) had three 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, 24/77 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=0.035), while the presence of >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.
