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Ultra-deep sequencing mutation analysis of the BCR/ABL1 kinase domain in newly diagnosed chronic myeloid leukemia patients

Authors
 Hyunkyung Park  ;  Inho Kim  ;  Hyeong-Joon Kim  ;  Dong-Yeop Shin  ;  Sung-Yeoun Lee  ;  Oh-Hyung Kwon  ;  Dae-Young Kim  ;  Kyoo-Hyung Lee  ;  Jae-Sook Ahn  ;  Jinny Park  ;  Sang-Kyun Sohn  ;  Jeong-Ok Lee  ;  June-Won Cheong  ;  Kyoung Ha Kim  ;  Hoon-Gu Kim  ;  Hawk Kim  ;  Yoo Jin Lee  ;  Seung-Hyun Nam  ;  Young Rok Do  ;  Sang-Gon Park  ;  Seong Kyu Park  ;  Sung Hwa Bae  ;  Hun Ho Song  ;  Doyeun Oh  ;  Chul Won Jung  ;  Seonyang Park 
Citation
 LEUKEMIA RESEARCH, Vol.111 : 106728, 2021-12 
Journal Title
LEUKEMIA RESEARCH
ISSN
 0145-2126 
Issue Date
2021-12
MeSH
Antineoplastic Combined Chemotherapy Protocols / therapeutic use* ; Biomarkers, Tumor / genetics* ; Dasatinib / administration & dosage ; Drug Resistance, Neoplasm / genetics* ; Female ; Follow-Up Studies ; Fusion Proteins, bcr-abl / genetics* ; High-Throughput Nucleotide Sequencing ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology* ; Male ; Middle Aged ; Mutation* ; Prognosis ; Prospective Studies ; Pyrimidines / administration & dosage ; Survival Rate
Keywords
BCR-ABL1 tyrosine kinase ; Chronic myeloid leukemia ; Molecular response ; Mutations ; Ultra-deep sequencing
Abstract
Ultra-deep sequencing detects low-frequency genetic mutations with high sensitivity. We used this approach to prospectively examine mutations in the BCR/ABL1 tyrosine kinase from patients with newly diagnosed, chronic-phase chronic myeloid leukemia (CML) treated with the tyrosine kinase inhibitor nilotinib. Between May 2013 and November 2014, 50 patients from 18 institutions were enrolled in the study. We screened 103 somatic mutations and found that mutations in the P-loop domain were the most frequent (173/454 mutations in the P-loop) and noted the presence of the V299 L mutation (dasatinib-resistant/nilotinib-sensitive) in 98 % of patients (49/50). No patients had Y253H, E255 V, or F359 V/C/I mutations, which would recommend dasatinib rather than nilotinib treatment. The S417Y mutation was associated with lower achievement of a major molecular response (MMR) at 6 months, and the V371A mutation was associated with reduced MMR and MR4.5 durations (MMR for 2 years: 100 % for no mutation vs. 75 % for mutation, P=0.039; MR4.5 for 15 months: 94.1 % vs. 25 %, P=0.002). Patients with known nilotinib-resistant mutations had lower rates of MR4.5 achievement. In conclusion, ultra-deep sequencing is a sensitive method for genetic-based treatment decisions. Based on the results of these mutational analyses, nilotinib treatment is a promising option for Korean patients with CML.
Full Text
https://www.sciencedirect.com/science/article/pii/S014521262101729X
DOI
10.1016/j.leukres.2021.106728
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Cheong, June-Won(정준원) ORCID logo https://orcid.org/0000-0002-1744-0921
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/190680
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