TY - JOUR
T1 - BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: A prospective study
AU - Von Bubnoff, Nikolas
AU - Schneller, Folker
AU - Peschel, Christian
AU - Duyster, Justus
N1 - Funding Information:
We thank Renyuan Bai and Cornelius Miething for technical advice; Claudia Mugler for technical assistance; and E Buchdunger and H Gschaidmeier (Novartis, Germany) for provision of STI571. This work was supported by a grant to J Duyster and C Peschel from the BMBF (Federal Ministry of Education and Research), German national genome project No 01-GS-0105 and 01-GS-0155.
PY - 2002/2/9
Y1 - 2002/2/9
N2 - 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. Findings 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. Interpretation 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.
AB - 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. Findings 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. Interpretation 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.
UR - http://www.scopus.com/inward/record.url?scp=0037045583&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(02)07679-1
DO - 10.1016/S0140-6736(02)07679-1
M3 - Journal articles
C2 - 11853795
AN - SCOPUS:0037045583
SN - 0140-6736
VL - 359
SP - 487
EP - 491
JO - Lancet
JF - Lancet
IS - 9305
ER -