TaeHyung Kim1, Marc S Tyndel2, Zhaolei Zhang3, Jaesook Ahn4, Seunghyun Choi4, Michael Szardenings5, Jeffrey H Lipton6, Hyeoung-Joon Kim7, Dennis Kim Dong Hwan6. 1. Department of Computer Science, University of Toronto, Toronto, ON, Canada; The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada. 2. The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; The Edward S. Rogers Sr. Department of Electrical and Computer Engineering, University of Toronto, Toronto, ON, Canada. 3. Department of Computer Science, University of Toronto, Toronto, ON, Canada; The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. Electronic address: zhaolei.zhang@utoronto.ca. 4. Hematopoietic Genomics Research Centre, Hwasun Chonnam National University Hospital, Chonnam National University, Hwasun, Republic of Korea. 5. Department of Cell Therapy, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany. 6. Department of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada. 7. Hematopoietic Genomics Research Centre, Hwasun Chonnam National University Hospital, Chonnam National University, Hwasun, Republic of Korea. Electronic address: hjoonk@chonnam.ac.kr.
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.
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 ABL1KD mutations. METHOD: We attempt to identify genetic markers associated with TKI therapy failure in 13 patients (5 resistant, 8 progressed) without ABL1KD 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 CMLpatients 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 ABL1KD 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 ABL1KD mutations.
Authors: Susan Branford; Dennis Dong Hwan Kim; Jane F Apperley; Christopher A Eide; Satu Mustjoki; S Tiong Ong; Georgios Nteliopoulos; Thomas Ernst; Charles Chuah; Carlo Gambacorti-Passerini; Michael J Mauro; Brian J Druker; Dong-Wook Kim; Francois-Xavier Mahon; Jorge Cortes; Jerry P Radich; Andreas Hochhaus; Timothy P Hughes Journal: Leukemia Date: 2019-06-17 Impact factor: 11.528
Authors: Alexander V Lavrov; Ekaterina Yu Chelysheva; Elmira P Adilgereeva; Oleg A Shukhov; Svetlana A Smirnikhina; Konstantin S Kochergin-Nikitsky; Valentina D Yakushina; Grigory A Tsaur; Sergey V Mordanov; Anna G Turkina; Sergey I Kutsev Journal: BMC Med Genomics Date: 2019-03-13 Impact factor: 3.063
Authors: Georgios Nteliopoulos; Alexandra Bazeos; Simone Claudiani; Gareth Gerrard; Edward Curry; Richard Szydlo; Mary Alikian; Hui En Foong; Zacharoula Nikolakopoulou; Sandra Loaiza; Jamshid S Khorashad; Dragana Milojkovic; Danilo Perrotti; Robert Peter Gale; Letizia Foroni; Jane F Apperley Journal: Haematologica Date: 2019-05-09 Impact factor: 9.941