| Description |
CML 1s caused by a random reciprocal translocation that joins the ABL1 gene on chromosome 9, with the BCR gene on chromosome 22. The result is the formation of the oncogenic BCR-ABL1 gene. This derivative chromosome is widely known as the Philadelphia Chromosome (Ph+), and it encodes a deregulated, constitutively activated tyrosine kinase called BCR-ABL1. Ponatinib is the only approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 point mutant-based resistance in Philadelphia chromosome-positive (Ph+) leukemia, including the highly resistant BCRABL1T3151 mutant. However, the development of compound mutants (2 mutations in the same BCR-ABL1 molecule) may inhibit ponatinib binding, and lead to treatment failure. We found that clinically reported BCR-ABL1 compound mutants center on 12 key positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib and bosutinib. T315I-inclusive compound mutants confer high-level TKI resistance, including to ponatinib. Structural explanations for compound mutation-based resistance were obtained through molecular dynamics simulations. Our findings demonstrate that BCR-ABL1 compound mutants present different levels of TKI resistance, requiring rational treatment selection to optimize clinical outcome. |
