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Blood, 15 May 2008, Vol. 111, No. 10, pp. 4930-4933.
Prepublished online as a Blood First Edition Paper on February 27, 2008; DOI 10.1182/blood-2008-01-117770.

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Brief Report

Structural and numerical variation of FLT3/ITD in pediatric AML

Soheil Meshinchi13, Derek L. Stirewalt1,4, Todd A. Alonzo3,5, Titus J. Boggon6, Robert B. Gerbing3, Jennifer L. Rocnik7, Beverly J. Lange3,6, D. Gary Gilliland7, and Jerald P. Radich1,4

1 Clinical Research Division, Fred Hutchinson Cancer Research Center, and 2 Department of Pediatrics, University of Washington Medical Center, Seattle; 3 Children's Oncology Group, Arcadia, CA; 4 Department of Medicine, University of Washington Medical Center, Seattle; 5 University of Southern California Keck School of Medicine, Los Angeles; 6 Department of Pharmacology, Yale University School of Medicine, New Haven, CT; and 7 Division of Hematology/Oncology, Department of Pathology, Brigham and Women's Hospital; the Howard Hughes Medical Institute, Harvard Medical School, Boston, MA

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.


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