BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: A prospective study

Nikolas Von Bubnoff, Folker Schneller, Christian Peschel, Justus Duyster*

*Corresponding author for this work
418 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalLancet
Volume359
Issue number9305
Pages (from-to)487-491
Number of pages5
ISSN0140-6736
DOIs
Publication statusPublished - 09.02.2002

Fingerprint

Dive into the research topics of 'BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: A prospective study'. Together they form a unique fingerprint.

Cite this