This Article Full Text Full Text (PDF) Koldehoff et al. Supplementary Appendix Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Koldehoff, M. Articles by Elmaagacli, A. H. PubMed PubMed Citation Articles by Koldehoff, M. Articles by Elmaagacli, A. H.

Small interfering RNA against BCR-ABL transcripts sensitize mutated T315I cells to nilotinib

¹ Department of Bone Marrow Transplantation, University Hospital of Duisburg-Essen, Essen and
² Departments of Haematology, Oncology and Gastroenterology, Clinics Maria Hilf, Mönchengladbach, Germany

Correspondence: Michael Koldehoff, MD, Department of Bone Marrow Transplantation, West German Cancer Center, University Hospital of Duisburg-Essen, Hufelandstr. 55 45122 Essen, Germany. E-mail: michael.koldehoff{at}uk-essen.de

Background: Selective inhibition of the BCR-ABL tyrosine kinase by RNA interference has been demonstrated in leukemic cells. We, therefore, evaluated specific BCR-ABL small interfering RNA silencing in BCR-ABL-positive cell lines, including those resistant to imatinib and particularly those with the T315I mutation.

Design and Methods: The factor-independent 32Dp210 BCR-ABL oligoclonal cell lines and human imatinib-resistant BCR-ABL-positive cells from patients with leukemic disorders were investigated. The effects of BCR-ABL small interfering RNA or the combination of BCR-ABL small interfering RNA with imatinib and nilotinib were compared with those of the ABL inhibitors imatinib and nilotinib.

Results: Co-administration of BCR-ABL small interfering RNA with imatinib or nilotinib dramatically reduced BCR-ABL expression in wild-type and mutated BCR-ABL cells and increased the lethal capacity. BCR-ABL small interfering RNA significantly induced apoptosis and inhibited proliferation in wild-type (P<0.0001) and mutated cells (H396P, T315I, P<0.0001) versus controls. Co-treatment with BCR-ABL small interfering RNA and imatinib or nilotinib resulted in increased inhibition of proliferation and induction of apoptosis in T315I cells as compared to imatinib or nilotinib alone (P<0.0001). Furthermore, the combination of BCR-ABL small interfering RNA with imatinib or nilotinib significantly (P<0.01) reversed multidrug resistance-1 gene-dependent resistance of mutated cells. In T315I cells BCR-ABL small interfering RNA with nilotinib had powerful effects on cell cycle distribution.

Conclusions: Our data suggest that silencing by BCR-ABL small interfering RNA combined with imatinib or nilotinib may be associated with an additive antileukemic activity against tyrosine kinase inhibitor-sensitive and resistant BCR-ABL cells, and might be an alternative approach to overcome BCR-ABL mutations.

Key words: small interfering RNA, CML, BCR-ABL.