%0 Journal Article
%T The oncogenic fusion protein RUNX1-CBFA2T1 supports proliferation and inhibits senescence in t(8;21)-positive leukaemic cells
%A Natalia Martinez
%A Bettina Drescher
%A Heidemarie Riehle
%A Claire Cullmann
%A Hans-Peter Vornlocher
%A Arnold Ganser
%A Gerhard Heil
%A Alfred Nordheim
%A J¨¹rgen Krauter
%A Olaf Heidenreich
%J BMC Cancer
%D 2004
%I BioMed Central
%R 10.1186/1471-2407-4-44
%X The t(8;21)-positive cell line Kasumi-1 was electroporated with RUNX1-CBFA2T1 or control siRNAs followed by analysis of proliferation, colony formation, cell cycle distribution, apoptosis and senescence.Electroporation of Kasumi-1 cells with RUNX1-CBFA2T1 siRNAs, but not with control siRNAs, resulted in RUNX1-CBFA2T1 suppression which lasted for at least 5 days. A single electroporation with RUNX1-CBFA2T1 siRNA severely diminished the clonogenicity of Kasumi-1 cells. Prolonged RUNX1-CBFA2T1 depletion inhibited proliferation in suspension culture and G1-S transition during the cell cycle, diminished the number of apoptotic cells, but induced cellular senescence. The addition of haematopoetic growth factors could not rescue RUNX1-CBFA2T1-depleted cells from senescence, and could only partially restore their clonogenicity.RUNX1-CBFA2T1 supports the proliferation and expansion of t(8;21)-positive leukaemic cells by preventing cellular senescence. These findings suggest a central role of RUNX1-CBFA2T1 in the maintenance of the leukaemia. Therefore, RUNX1-CBFA2T1 is a promising and leukaemia-specific target for molecularly defined therapeutic approaches.The chromosomal translocation t(8;21) (q22;q22), which is associated with 10¨C15% of all cases of acute myeloid leukaemia, fuses the DNA binding domain of the transcription factor RUNX1 (also called AML1 or CBF¦Á) to the almost complete open reading frame of CBFA2T1 (also named MTG8 or ETO) [1,2]. The resulting fusion protein RUNX1-CBFA2T1 (AML1/MTG8, AML1/ETO) interferes with haematopoetic gene expression by recruiting histone deacetylases via N-CoR and mSin3 to promoters, thereby inhibiting the transcription of the respective target gene [3-7]. Moreover, by directly binding to and sequestering transcription factors, such as SMAD3, C/EBP¦Á or vitamin D receptor, RUNX1-CBFA2T1 interferes with signal transduction pathways controlling differentiation and proliferation [8-12]. Consequently, RUNX1-CBFA2T1 blocks myeloid different
%U http://www.biomedcentral.com/1471-2407/4/44