title: Additive antileukemia effects by GFI1B- and BCR-ABL-specific siRNA in advanced phase chronic myeloid leukemic cells.
abstract: Previous studies demonstrated selective inhibition of the BCR-ABL (breakpoint cluster region-Abelson murine leukemia oncogene) tyrosine kinase by RNA interference in leukemic cells. In this study, we evaluated the effect of BCR-ABL small interfering RNA (siRNA) and GFI1B siRNA silencing on chronic myeloid leukemia (CML) cells in myeloid blast crises. The GFI1B gene was mapped to chromosome 9 and is, therefore, located downstream of the BCR-ABL translocation in CML cells. Co-transfection of BCR-ABL siRNA and GFI1B siRNA dramatically decreased cell viability and significantly induced apoptosis and inhibited proliferation in K562 cells (P<0.0001) and primary advanced phase CML cells (P<0.0001) versus controls. Furthermore, combining of BCR-ABL siRNA and GFI1B siRNA significantly modified the expression of several relevant genes including Myc, MDR1, MRP1 and tyrosyl-phosphoproteins in primary CML cells. Our data suggest that silencing of both BCR-ABL siRNA and GFI1B siRNA is associated with an additive antileukemic effect against K562 cells and primary advanced CML cells, further validating these genes as attractive therapeutic targets.
authors.affiliation: Department of Bone Marrow Transplantation, West German Cancer Center, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany. michael.koldehoff@uk-essen.de
authors.forename: M
authors.initials: M
authors.lastname: Koldehoff
authors.forename: J L
authors.initials: JL
authors.lastname: Zakrzewski
authors.forename: D W
authors.initials: DW
authors.lastname: Beelen
authors.forename: A H
authors.initials: AH
authors.lastname: Elmaagacli
mesh_terms: D017209:Apoptosis; D049109:Cell Proliferation; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C111977:GFI1B protein, human; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D016044:Fusion Proteins, bcr-abl