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

Meshinchi, Soheil and Stirewalt, Derek L and Alonzo, Todd A and Boggon, Titus J and Gerbing, Robert B and Rocnik, Jennifer L and Lange, Beverly J and Gilliland, D Gary and Radich, Jerald P (2008) Structural and numerical variation of FLT3/ITD in pediatric AML. Blood, 111 (10). pp. 4930-4933. ISSN 1528-0020

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.

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