Exome sequencing reveals DNMT3A and ASXL1 variants associate with progression of chronic myeloid leukemia after tyrosine kinase inhibitor therapy

Abstract

ObjectiveThe development of tyrosine kinase inhibitors (TKIs) has significantly improved the treatment of chronic myeloid leukemia (CML). However, approximately one third of patients are resistant to TKI and/or progress to advanced disease stages. TKI therapy failure has a well-known association with ABL1 kinase domain (KD) mutations, but only around half of TKI non-responders have detectable ABL1 KD mutations. MethodWe attempt to identify genetic markers associated with TKI therapy failure in 13 patients (5 resistant, 8 progressed) without ABL1 KD mutations using whole-exome sequencing. ResultsIn 6 patients, we detected mutations in 6 genes commonly mutated in other myeloid neoplasms: ABL1, ASXL1, DNMT3A, IDH1, SETBP1, and TP63. We then used targeted deep sequencing to validate our finding in an independent cohort consisting of 100 CML patients with varying drug responses (74 responsive, 18 resistant, and 8 progressed patients). Mutations in genes associated with epigenetic regulations such as DNMT3A and ASXL1 seem to play an important role in the pathogenesis of CML progression and TKI-resistance independent of ABL1 KD mutations. ConclusionThis study suggests the involvement of other somatic mutations in the development of TKI resistant progression to advanced disease stages in CML, particularly in patients lacking ABL1 KD mutations.