Characteristics of BCR-ABL kinase domain point mutations in Chinese imatinib-resistant chronic myeloid leukemia patients.
To explore the characteristics of BCR-ABL kinase domain point mutations in Chinese chronic myeloid leukemia (CML) patients, a cohort of 127 patients with hematologic or cytogenetic resistance to imatinib are screened by direct sequencing. Mutations are found in 74 patients (58%). More patients with hematologic resistance show mutations compared to patients with cytogenetic resistance (70% vs 44%, p = 0.002), and more patients with acquired resistance present mutations compared to patients with primary resistance (68% vs 48%, p = 0.031). Frequencies of mutations were similar in early chronic phase (ECP), late chronic phase (LCP), accelerated phase, and blast phase (BP) patients (56%, 58%, 50%, and 69%, respectively; p > 0.05). Overall, 25 mutants are found in 21 amino acid sites, and four of them (I418V, E450A, E453L, and E455K) are first reported here. All patients with these four mutants either progress to or reenter the BP. The most frequent mutant is M244V, followed by Y253H, F359C/V/I, G250E, E255K, and T315I. Only seven patients (9%) have T315I mutants, and all showed hematologic resistance. Three of them were in the ECP and three in the LCP. Look-back studies show that mutants were detected 0-20 (median 7) months ahead of the appearance of clinical resistance in 15 tested patients with acquired resistance. ABL mutations are common in Chinese imatinib-resistant CML patients and are associated with clinical resistance. Chinese patients also seem to have unique profiles in the types and frequencies of some mutants, the disease phases of patients with T315I mutation, and the frequency of mutations in CP patients.
Qin
Yazhen
Y
Institute of Hematology, People's Hospital of Peking University, 11 Xi-zhi-men South Street, Beijing, People's Republic of China, 100044.
Chen
Shanshan
S
Jiang
Bin
B
Jiang
Qian
Q
Jiang
Hao
H
Li
Jinlan
J
Li
Lingdi
L
Lai
Yueyun
Y
Liu
Yanrong
Y
Huang
Xiaojun
X
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics; D001549:Benzamides; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics*; D016313:Genes, abl / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010770:Phosphotransferases / Q000737:chemistry / Q000235:genetics; D010879:Piperazines / Q000627:therapeutic use*; D017354:Point Mutation; D017434:Protein Structure, Tertiary / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use*; D055815:Young Adult
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D010770:Phosphotransferases; D016044:Fusion Proteins, bcr-abl