D324N single-nucleotide polymorphism in the FLT3 gene is associated with higher risk of myeloid leukemias

✍ Scribed by Susanne Schnittger; Tobias M. Kohl; Nina Leopold; Claudia Schoch; H.-Erich Wichmann; Wolfgang Kern; Peter Lohse; Wolfgang Hiddemann; Torsten Haferlach; Karsten Spiekermann

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: English
• Weight: 192 KB
• Volume: 45
• Category: Article
• ISSN: 1045-2257
• DOI: 10.1002/gcc.20294

✦ Synopsis

Abstract

Mutations within the FLT3 gene are of growing importance for classification, risk assessment, and therapeutic targeting of acute myeloid leukemia (AML). We analyzed 656 AML patients for a recently described single‐nucleotide polymorphism (SNP) in the third immunoglobulin‐like domain of the extracellular region of FLT3. The FLT3 D324N variant was present in 42 cases (6.4%), but it was not associated with a specific AML subtype and did not show an elevated leukocyte count, as do other FLT3 mutations. In remission samples, a 50% ratio of the normal to the D324N variant was detectable. Stably expressed in IL‐3 dependent Ba/F3 cells, the D324N variant did not confer receptor autophosphorylation, factor independent growth, or increased resistance to apoptotic cell death in response to varying doses of FLT3 ligand. In 400 healthy donors, the FLT3 D324N variant was detected in 6 cases (1.5%) and segregated in a family. Thus, it was shown to be a polymorphism with a lower frequency in healthy controls than in patients with AML (P < 0.001). In addition, 21 of 234 CML (9.0%) and 7 of 155 ALL (4.5%) cases carried the FLT3 D324N. Our data suggest that the FLT3 D324N variant might be associated with a predisposition to different subtypes of leukemia. © 2005 Wiley‐Liss, Inc.