Point mutations at the ATP-binding site of the ABL kinase.

A 714-bp region of ABL that codes for the ATP-binding site and the kinase activation loop was PCR amplified using 2 primer pairs and directly sequenced in 30 complementary DNAs (including 9 paired samples) obtained from the bone marrow of individuals with Ph⁺ ALL. Sequencing revealed a single point mutation at nucleotide 1127 (GI6382056) changing a G to an A resulting in Glu255Lys. This mutation was found in 6 samples from patients who where treated with STI571 (nos. 1, 2, 4, 5, 15, 16) but not in any other sample including paired samples from the same individuals before treatment with STI571. (Top) Schematic protein structure of ABL including the amino acid sequence for the highly conserved ATP-binding site motif (underlined). The nucleotide sequence corresponding to Glu255, which is affected by the mutation is marked by a rectangle. The left hand column contains the patient number; wt indicates wild-type ABL.