Exome sequencing reveals DNMT3A and ASXL1 variants associate with progression of chronic myeloid leukemia after tyrosine kinase inhibitor therapy. (August 2017)

• Record Type: Journal Article
• Authors: Kim, TaeHyung; Tyndel, Marc S.; Zhang, Zhaolei; Ahn, Jaesook; Choi, Seunghyun; Szardenings, Michael; Lipton, Jeffrey H.; Kim, Hyeoung-Joon; Kim Dong Hwan, Dennis
• Is Part Of: Leukemia research. Volume 59(2017:Aug.)
• Page Start: 142
• Page End: 148
• Publication Date: 2017-08
• Subjects: Chronic myeloid leukemia -- Tyrosine kinase inhibitor -- Drug resistance -- Whole exome sequencing; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2017.06.009
• Languages: English
• ISSNs: 0145-2126

Abstract

Highlights: Acquisition of somatic mutation is associated with TKI therapy failure and progression in CML patients. Exome sequencing revealed mutations in 6 genes: ABL1, ASXL1, DNMT3A, IDH1, SETBP1, and TP63. Somatic mutations is responsible for TKI resistance esp. lacking ABL1 KD mutations. Abstract: Objective: The 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. Method: We 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. Results: In 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. Conclusion: This 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.