A model to investigate the oncogenic activity of MLL-fusions in Acute Myeloid Leukaemia

摘要: The MLL gene, located on 11q23, is involved in a large number of chromosomal translocations, including t(9;11)(p22;q23) and t(11;19)(p22;q23). These translocations encode the MLL-AF9 MLL-ENL fusion transcription factors are prevalent infant acute leukaemia therapy-related leukaemia. Leukaemias associated with these have particularly poor outcome. In order to conditionally express oncogene primary haematopoietic progenitor cells, retroviral delivery Tet-off expression system was used. Progenitors were purified from murine bone marrow co-infected with MSCV-TRE-fMLL-AF9 MSCV-tTA supernatants. Using this approach, eight independent cell lines conditional and three constitutive generated. Treatment cells Doxycycline caused decrease MLL-AF9 mRNA protein expression, resulted terminal differentiation cells. By analysing global changes gene after treatment with Doxycycline, using Mouse genome Affymetrix Gene Chips (430 2.0), we have identified potential transcriptional target genes and MLL-ENL oncogenes. In order examine importance for MLL-fusion mediated transformation, up-regulated knocked down in vitro. Knock-down small proportion analysed caused MLL-ENL immortalised die. These data illustrate novel approaches interfering MLL-fusion activity leukaemia. to establish for vivo, hence its dependence identified, immortalised cell chosen be injected into primary recipients. Conditionally found induced vivo. Leukaemic cells isolated recipient mice shown acquired additional genetic abnormalities and, when transplanted secondary recipients, induced leukaemia shortened latencies. However, leukaemic remained dependent vitro its ablation in regression established leukaemias.