BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study.
BACKGROUND
BCR-ABL, a constitutively activated tyrosine kinase, is the oncogene that causes Philadelphia-chromosome-positive (Ph+) leukaemia. STI571, a competitive inhibitor at the ATP-binding site of BCR-ABL, has been shown to have high activity in this type of leukaemia. However, most patients with advanced disease relapse despite continued treatment with STI571. We aimed to find out whether point mutations in BCR-ABL cause resistance to STI571.


METHODS
We analysed clinical samples from eight patients resistant to STI571-who had advanced-stage Ph+ leukaemia-for mutations within the ATP-binding site and activation loop of BCR-ABL. Analysis was done before treatment with STI571 and at time of relapse.


RESULTS
We identified five distinct point mutations in the BCR-ABL kinase domain in seven patients. All point mutations arose at positions that have proved to be important for drug binding and have conferred resistance to STI571 in vitro. All patients with mutations had lymphoid leukaemia.


CONCLUSIONS
Different mutations within the kinase domain of BCR-ABL can be responsible for refractoriness of Ph+ leukaemia to STI571. Mutation in the BCR-ABL kinase domain might be a frequent mechanism of STI571 resistance in lymphoid disease.
von Bubnoff
Nikolas
N
Department of Internal Medicine III, Laboratory of Leukemogenesis, Technical University of Munich, Ismaningerstrasse 22, 81675, Munich, Germany.
Schneller
Folker
F
Peschel
Christian
C
Duyster
Justus
J
D001549:Benzamides; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D010879:Piperazines; D017354:Point Mutation; D011446:Prospective Studies; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl