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: M Koldehoff, J L Zakrzewski, D W Beelen, A H Elmaagacli
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 20 Issue 7 Pg. 421-7 (Jul 2013) ISSN: 1476-5500 [Electronic] England
• PMID: 23788109 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GFI1B protein, human
• Proto-Oncogene Proteins
• RNA, Small Interfering
• Repressor Proteins
• Fusion Proteins, bcr-abl

Topics

• Apoptosis
• Cell Proliferation
• Fusion Proteins, bcr-abl (genetics, metabolism)
• Gene Expression
• Gene Knockdown Techniques
• Hematopoietic Stem Cells (metabolism)
• Humans
• K562 Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Proto-Oncogene Proteins (genetics, metabolism)
• RNA Interference
• RNA, Small Interfering (genetics)
• Real-Time Polymerase Chain Reaction
• Repressor Proteins (genetics, metabolism)