[Detection of ABL kinase domain point mutations in chronic myeloid leukemia patients receiving imatinib treatment].
OBJECTIVE
To analyze the frequency and clinical significance of ABL tyrosine kinase point mutations in chronic myeloid leukemia (CML) patients receiving imatinib treatment.


METHODS
Nested reverse transcriptase-polymerase chain reaction (RT-PCR) was performed on 40 bone marrow samples from 23 patients to amplify the ABL kinase domain, followed by direct sequencing and sequence homologous analysis.


RESULTS
In the 23 patients analyzed, the ABL domain point mutations was detected in 7 patients who presented with 5 types of nucleotide changes, namely T315I(n=3), Y253H, E255K, F317L and G321W. The incidence of mutations in chronic phase (CP), accelerated phase (AP) and blast phase (BP) was 25.00%, 40.00% and 30.00%, respectively. For 6 of the 7 patients with mutations who were resistant to imatinib before sequencing, the daily drug dose had been increased to 600-800 mg daily for poor response to 400 mg/day imatinib. During the follow-up for 3-6 months, only the patient with F317L achieved major cytogenetic response (MCR), and the patient with Y253H and 1 of the 3 with T315I progressed to BP. The newly diagnosed patient with G321W IN cp achieved a complete hematologic remission and had a significant decrease of the proportion of BCR-ABL-positive cells.


CONCLUSIONS
ABL kinase point mutation is an important mechanism of imatinib resistance. The type of mutations is associated with the level of resistance to imatinib, and detection of ABL kinase point mutations by direct sequencing may help estimate the prognosis and plan for therapeutic strategy adjustment.
Ouyang
Zhao
Z
Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. ouyangzhao82@yahoo.com.cn
DU
Qing-feng
QF
Liu
Xiao-li
XL
Zhang
Song
S
Zhu
Hong-qian
HQ
Gong
Jun-mei
JM
Song
Lan-lin
LL
Ouyang
Ling-yun
LY
Liu
Zhi
Z
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001483:Base Sequence; D001549:Benzamides; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D010879:Piperazines / Q000627:therapeutic use*; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases