Specific inhibition of bcr-abl gene expression by small interfering RNA.
Small interfering RNAs (siRNAs) were designed to target the bcr-abl oncogene, which causes chronic myeloid leukemia (CML) and bcr-abl-positive acute lymphoblastic leukemia (ALL). Chemically synthesized anti-bcr-abl siRNAs were selected using reporter gene constructs and were found to reduce bcr-abl mRNA up to 87% in bcr-abl-positive cell lines and in primary cells from CML patients. This mRNA reduction was specific for bcr-abl because c-abl and c-bcr mRNA levels remained unaffected. Furthermore, protein expression of BCR-ABL and of laminA/C was reduced by specific siRNAs up to 80% in bcr-abl-positive and normal CD34(+) cells, respectively. Finally, anti-bcr-abl siRNA inhibited BCR-ABL-dependent, but not cytokine-dependent, proliferation in a bcr-abl-positive cell line. These data demonstrate that siRNA can specifically and efficiently interfere with the expression of an oncogenic fusion gene in hematopoietic cells.
Scherr
Michaela
M
Department of Hematology and Oncology, Hannover Medical School, Germany. m.scherr@t-online.de
Battmer
Karin
K
Winkler
Thomas
T
Heidenreich
Olaf
O
Ganser
Arnold
A
Eder
Matthias
M
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000032:analysis / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects*; D049452:Green Fluorescent Proteins; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D034904:Lamin Type A / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008856:Microscopy, Fluorescence; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured
D016207:Cytokines; D034904:Lamin Type A; D008164:Luminescent Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C440308:lamin C; D049452:Green Fluorescent Proteins; D016044:Fusion Proteins, bcr-abl