BCR-ABL1 compound mutations in tyrosine kinase inhibitor resistant CML: frequency and clonal relationships
Menée sur 47 échantillons tumoraux prélevés sur des patients atteints d'une leucémie myéloïde chronique, cette étude met en évidence des mutations composites de BCR-ABL1 associées à une résistance thérapeutique
BCR-ABL1 compound mutations can confer high-level resistance to imatinib and other ABL1 tyrosine kinase inhibitors (TKIs). The third generation ABL1 TKI, ponatinib, is effective against BCR-ABL1 point mutants individually but remains vulnerable to certain BCR-ABL1 compound mutants. To determine the frequency of compound mutations among CML patients on ABL1 TKI therapy, we examined a collection of patient samples (N=47) with clear evidence of two BCR-ABL1 kinase domain mutations by direct sequencing. Using a cloning and sequencing method, we found that 70% (33/47) of double mutations detected by direct sequencing were compound mutations. Sequential, branching, and parallel routes to compound mutations were common. Additionally, our approach revealed individual and compound mutations not detectable by direct sequencing. The frequency of clones harboring compound mutations with more than two missense mutations was low (10%), while the likelihood of silent mutations increased disproportionately with the total number of mutations per clone, suggesting a limited tolerance for BCR-ABL1 kinase domain missense mutations. We report that compound mutations are common in patients with sequencing evidence for two BCR-ABL1 mutations and frequently reflect a highly complex clonal network whose evolution may be limited by the negative impact of missense mutations on kinase function.