Kinase domain point mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia emerge after therapy with BCR-ABL kinase inhibitors

Abstract

Background: BCR-ABL kinase domain (KD) mutations are detected in approximately 45% of patients with imatinib-resistant chronic myeloid leukemia. Patterns of KD mutations in Philadelphia chromosome (Ph)-positive acute lympho- blastic leukemia (ALL) are less well studied.

Methods: The authors assessed KD mutations in patients with recurrent Ph-positive ALL after treatments that included 1 or more kinase inhibitors (n = 24 patients) or no prior kinase inhibitor (KI) therapy (n = 12 patients).

Results: ABL KD mutations were detected by direct sequencing in 15 of 17 patients (88%) who had recurrent Ph-positive ALL and received prior imatinib (n = 16) or dasatinib (n = 1) treatment and in 6 of 7 patients (86%) who had resistant/recurrent tumors treated with >or=2 KIs compared with 0 of 12 patients with recurrent Ph-positive ALL who never received KIs. A restricted set of mutations was observed, mostly Y253H and T315I, and were detected on average 10 months after KI initiation, and mutations were not detected in the initial tumor samples before KI therapy in 12 patients who were assessed. Using a more sensitive pyrosequencing method, mutations were not detected at codons 315 and 253 in the diagnostic samples from those 12 patients or in 30 patients with Ph-positive ALL who never developed recurrent disease.

Conclusions: ABL KD mutations, especially at codons 315 and 253, emerged at the time of disease recurrence in the vast majority of patients who had Ph-positive ALL and received maintenance KI therapy. Thus, the authors concluded that ongoing KI exposure may alter the patterns of recurrence and favor the outgrowth of clones with KI-resistant mutations.

Figure 1. Summary of location of mutations in the kinase domain of BCR-ABL in relapsed Ph+ ALL

Illustrated is a schematic representation of the kinase domain, including ATP binding pocket (P-loop), catalytic domain (C), and activation loop (A). Mutations which developed on imatinib are shown as open circles, those developing on dasatinib as black circles or triangles, and those on nilotinib and bosutinib as hatched circles. The hatched lines indicate the area covered by the pyrosequencing (pyro) mutation assay. Amino acid designation for the mutations are those of the ABL type 1a protein, with the following approximate KD subdomains: P-loop 248–256, C-helix/catalytic domain 276–290, SH3 contact 294–304, additional imatinib binding pocket 311-318, SH2 contact 331–353, and activation loop 381–402.

Figure 2. Mapping of BCR-ABL KD mutations seen in relapsed Ph+ ALL

Human Abl kinase domain in complex with imatinib (accession 2HYY, accessed from the RCSB Protein Data Bank), was rendered with MBT protein workshop software. One ABL chain is shown, with imatinib in its binding pocket highlighted in purple; ABL codon 253 is labeled green, codon 315 is red, codon 317 is yellow, and codon 355 is blue.