[Analysis of ABL tyrosine kinase point mutations in imatinib treated chronic myelogenous leukemia patients].
OBJECTIVE
To evaluate ABL tyrosine kinase point mutations in imatinib treated chronic myelogenous leukemia (CML) patients.


METHODS
A total of 45 bone marrow samples from 30 CML patients were included in this work. The patients were in accelerated/blast phase (AP/BP) or late-chronic phase (CP) at the start of imatinib and usually showed resistance to imatinib. ABL kinase domain of BCR-ABL allele was amplified by nested reverse transcriptase-polymerase chain reaction technique, followed by direct sequencing and sequence homologous analyzing.


RESULTS
The ABL point mutation was detected in 13 of 30 patients, 12 of them had progressed to advanced phase, The other patient who was in late chronic phase showed point mutation when she was at 45th months of imatinib treatment, but she was still in complete cytogenetic remission at 50th months and is doing well. 4 patients had Glu255Lys mutation and 4 had Gly250Glu, the other types of mutation were Phe359Cys, Glu355Gly, Met244Val, Tyr253His and Asp276Gly, each was tested in one patient. 11/12 patients who progressed to advanced disease and showed point mutation were collected samples in advanced stage, 8 patients showed homozygote mutation, and 3 patients had a mixture of wild and mutant type. In advanced stage patients, mutations were detected in a median of 5 months (ranged 0.5-30 months), it appeared much earlier than that in late CP patients (25.5 months, ranged 11-45 months, P < 0.05). In 4/7 followed up patients, the intensity of point mutation increased gradually within 7-15 months before disease progression. 6 patients did not showed ABL point mutation while their disease were in progression.


CONCLUSIONS
Abl kinase point mutation is one of the main mechanisms of CML secondary resistance to imatinib. Long term regular monitoring of ABL kinase point mutation is necessary during imatinib treatment.
Qin
Ya-zhen
YZ
Institute of Hematology, People's Hospital of Peking University, Beijing 100044, China.
Liu
Yan-rong
YR
Li
Jin-lan
JL
Ruan
Guo-rui
GR
Zhu
Hong-hu
HH
Jiang
Qian
Q
Fu
Jia-yu
JY
Lu
Ying
Y
Chang
Yan
Y
Li
Ling-di
LD
Huang
Xiao-jun
XJ
Chen
Shan-shan
SS
Qiu
Jing-ying
JY
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001483:Base Sequence; D001549:Benzamides; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use*; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl