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. 2008 May 15;111(10):4930-3.
doi: 10.1182/blood-2008-01-117770. Epub 2008 Feb 27.

Structural and numerical variation of FLT3/ITD in pediatric AML

Soheil Meshinchi  1 , Derek L Stirewalt, Todd A Alonzo, Titus J Boggon, Robert B Gerbing, Jennifer L Rocnik, Beverly J Lange, D Gary Gilliland, Jerald P Radich
Affiliations

Structural and numerical variation of FLT3/ITD in pediatric AML

Soheil Meshinchi et al. Blood. .

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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Figures

Figure 1
Figure 1
Region of duplication in FLT3/ITD. (A) Proportion of patients with involvement of specific aa residues in the duplicated region. Codons 591 to 597 are shown in darker bars, and specific aa residues in this region are shown in the center inset. (B) The region of duplication in all 77 patients are sorted by ITD length (longest to shortest) from top to bottom. The area of duplication of the major ITD peak is shown in dark highlighted area. In patients with additional ITDs, the duplicated region is shown in red with the area of overlap in blue. Codons 591 to 597 are shown in shaded box. (C) FLT3 structure showing the location of the JM domain and Y597. Ribbon representation of the crystal structure of FLT3 previously solved by Griffith et al. The kinase domain N-lobe is colored green and the C-lobe, blue. The activation loop is colored orange and the JM domain, yellow. Tyrosines 597, 591, and 589 are shown in stick format. The exploded view shows the molecular surface of the kinase domain and JM domain side-chain residues Y591 to Y597. Tyrosine 597 is depicted with space-filling spheres. This figure was made using the program Pymol (www.pymol.org).
Figure 2
Figure 2
Clinical outcome for FLT3/ITD-positive patients with high versus low ITD length based on ITD length threshold of 48 bp. (A) Overall survival from study entry. (B) Relapse-free survival from complete remission.
See this image and copyright information in PMC

References

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