1. The oncogenic fusion protein RUNX1-CBFA2T1 supports proliferation and inhibits senescence in t(8;21)-positive leukaemic cells
- Author
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Natalia Martinez, Bettina Drescher, Jürgen Krauter, Alfred Nordheim, Arnold Ganser, Claire Cullmann, Olaf Heidenreich, Heidemarie Riehle, Hans-Peter Vornlocher, and Gerhard Heil
- Subjects
Senescence ,Cancer Research ,Cell division ,Antigens, CD34 ,Apoptosis ,Biology ,lcsh:RC254-282 ,RUNX1 Translocation Partner 1 Protein ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,Genetics ,Humans ,RNA, Small Interfering ,Cellular Senescence ,Cell growth ,Cell cycle ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Clone Cells ,Hematopoiesis ,Cell biology ,DNA-Binding Proteins ,Haematopoiesis ,Oncology ,Leukemia, Myeloid ,Cell culture ,Core Binding Factor Alpha 2 Subunit ,embryonic structures ,Stem cell ,Cell aging ,Cell Division ,Research Article ,Transcription Factors - Abstract
Background The fusion protein RUNX1-CBFA2T1 associated with t(8;21)-positive acute myeloid leukaemia is a potent inhibitor of haematopoetic differentiation. The role of RUNX1-CBFA2T1 in leukaemic cell proliferation is less clear. We examined the consequences of siRNA-mediated RUNX1-CBFA2T1 depletion regarding proliferation and clonogenicity of t(8;21)-positive cell lines. Methods 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. Results 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. Conclusions 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.
- Published
- 2004