Inhibition of bcr-abl gene expression by small interfering RNA sensitizes for imatinib mesylate (STI571)

Bcr-Abl proteins are effective inducers of the leukemic phenotype in chronic myeloid leukemia (CML) and distinct variants of acute lymphoblastic leukemia (ALL). Targeting bcr-abl by treatment with the selective tyrosine kinase inhibitor imatinib has proved to be highly efficient for controlling leuk...

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Bibliographic Details
Published in:Blood 2003-09, Vol.102 (6), p.2236-2239
Main Authors: Wohlbold, Lara, van der Kuip, Heiko, Miething, Cornelius, Vornlocher, Hans-Peter, Knabbe, Cornelius, Duyster, Justus, Aulitzky, Walter E.
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - pharmacology
Benzamides
Biological and medical sciences
Cell Division - drug effects
Cell Survival - drug effects
Chemotherapy
Drug Resistance, Neoplasm
Fusion Proteins, bcr-abl - genetics
Gene Expression Regulation, Leukemic - drug effects
Humans
Imatinib Mesylate
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics
Medical sciences
Pharmacology. Drug treatments
Piperazines - pharmacology
Pyrimidines - pharmacology
RNA, Small Interfering - pharmacology
Tumor Cells, Cultured
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Summary:Bcr-Abl proteins are effective inducers of the leukemic phenotype in chronic myeloid leukemia (CML) and distinct variants of acute lymphoblastic leukemia (ALL). Targeting bcr-abl by treatment with the selective tyrosine kinase inhibitor imatinib has proved to be highly efficient for controlling leukemic growth. However, it is unclear whether imatinib is sufficient to eradicate the disease because of primary or secondary resistance of leukemic cells. Therefore, targeting Bcr-Abl with an alternative approach is of great interest. We demonstrate that RNA interference (RNAi) with a breakpoint-specific short-interfering RNA (siRNA) is capable of decreasing Bcr-Abl protein expression and of antagonizing Bcr-Abl–induced biochemical activities. RNAi selectively inhibited Bcr-Abl–dependent cell growth. Furthermore, bcr-abl–homologous siRNA increased sensitivity to imatinib in Bcr-Abl–overexpressing cells and in a cell line expressing the imatinib-resistant Bcr-Abl kinase domain mutation His396Pro, thereby antagonizing 2 of the major mechanisms of resistance to imatinib.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2002-12-3899