[The monitoring of residual disease for chronic myelogenous leukemia patients treated with imatinib mesylate: detection of T315I mutation in ATP binding site of BCR/ABL gene].
Imatinib Mesylate, a specific inhibitor of BCR/ABL tyrosine kinase, was developed as a molecularly targeted drug for the treatment of patients with chronic myelogenous leukemia. We evaluated effectiveness of the drug on cytogenetic response for monitoring residual disease using fluorescence in situ hybridization(FISH), reverse transcription-nested-polymerase chain reaction(RT-nested-PCR) and competitive PCR strategy. Of 9 patients in chronic phase, 7 achieved major cytogenetic response(CR) and 2 achieved minor CR by FISH. In 3 out of 6 patients with complete CR, no BCR/ABL gene was detected by RT-nested-PCR in peripheral blood or bone marrow specimens. Of 4 patients in accelerated phase, 1 achieved complete CR but 3 developed blast crisis. Despite high efficacy of Imatinib, 5 out of 13 patients showed resistance to the drug. To clarify the mechanism of resistance, we have newly developed a method for investigating a point mutation of T315I in tyrosine kinase domain of BCR/ABL gene using RT-PCR restriction digested analysis. None of them showed T315I mutation. The sensitivity of the method was as low as 10 copies of mutant gene. The method is useful for screening the mutation when there are many clinical samples or low copy number of BCR/ABL gene. BCR/ABL value obtained by FISH was of use to predict cytogenetic response when residual disease was above 2 to 3%. Below this level, the routine use of RT-nested-PCR was suffices to monitor minimal residual disease.
Miyanishi
Setsuko
S
Tenri Institute of Medical Research, Tenri 632-8552.
Umeki
Kazumi
K
Hayashi
Takamasa
T
Fukutsuka
Katsuhiro
K
Okumura
Atsuko
A
Kishimori
Chiyuki
C
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000328:Adult; D000368:Aged; D001549:Benzamides; D001665:Binding Sites / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis* / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018365:Neoplasm, Residual / Q000175:diagnosis / Q000235:genetics; D010879:Piperazines / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl