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<https://discovery.ucl.ac.uk/id/eprint/18608> <http://purl.org/dc/terms/title> "A model to investigate the oncogenic activity of MLL-fusions in Acute Myeloid Leukaemia"^^<http://www.w3.org/2001/XMLSchema#string> .
<https://discovery.ucl.ac.uk/id/eprint/18608> <http://purl.org/ontology/bibo/abstract> "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).\r\nThese translocations encode the MLL-AF9 and MLL-ENL fusion transcription\r\nfactors and are prevalent in infant acute leukaemia and therapy-related leukaemia.\r\nLeukaemias associated with these translocations have a particularly poor outcome. In\r\norder to conditionally express the MLL-AF9 fusion oncogene in primary\r\nhaematopoietic progenitor cells, retroviral delivery of the Tet-off expression system\r\nwas used. Progenitors were purified from murine bone marrow and co-infected with\r\nMSCV-TRE-fMLL-AF9 and MSCV-tTA retroviral supernatants. Using this\r\napproach, eight independent cell lines with conditional expression of MLL-AF9 and\r\nthree independent cell lines with constitutive MLL-AF9 expression were generated.\r\nTreatment of the conditional cells with Doxycycline caused a decrease in MLL-AF9\r\nmRNA and protein expression, and resulted in terminal differentiation of the cells.\r\nBy analysing global changes in gene expression after treatment of cells with\r\nDoxycycline, using Mouse genome Affymetrix Gene Chips (430 2.0), we have\r\nidentified a number of potential transcriptional target genes of the MLL-AF9 and\r\nMLL-ENL fusion oncogenes. In order to examine the importance of target genes for\r\nMLL-fusion mediated transformation, up-regulated target genes were knocked down\r\nin vitro. Knock-down of a small proportion of the target genes analysed caused\r\nMLL-ENL and MLL-AF9 immortalised cells to die. These data illustrate novel\r\napproaches to interfering with MLL-fusion activity in leukaemia. In order to\r\nestablish the importance of MLL-fusion activity for leukaemia in vivo, and hence its\r\ndependence on the transcriptional target genes identified, MLL-ENL immortalised\r\ncell lines were chosen to be injected into primary recipients. Conditionally MLL-ENL immortalised cell lines were found to induced leukaemia in vivo. Leukaemic\r\ncells isolated from primary recipient mice were shown to have acquired additional\r\ngenetic abnormalities and, when transplanted into secondary recipients, induced\r\nleukaemia with shortened latencies. However, the leukaemic cells remained\r\ndependent on MLL-ENL expression in vitro and in vivo, and its ablation resulted in\r\nregression of established leukaemias."^^<http://www.w3.org/2001/XMLSchema#string> .
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