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Title: The role of fusion proteins in leukaemogenesis
Author: Dobson, C. L.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2000
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A mouse model of the Mll-AF9 gene fusion was made in embryonic stem cells by an homologous recombination knock-in. Acute leukaemia developed in both chimaeras and heterozygous mice carrying this fusion. As with human chromosomal translocation t(9;11), the majority of cases were acute myeloblastic leukaemias, but a minority were acute lymphoblastic leukaemia. The acute myeloid leukaemias were preceded by effects on haematopoietic differentiation involving a myeloproliferation resulting in accumulation of Mac-1+/Gr-1+ mature myeloid cells in bone marrow as early as 6 days after birth. Therefore non-malignant expansion of myeloid precursors is the first stage of M11-AF9 mediated leukaemia followed by accumulation of malignant cells in bone marrow and other tissue sites. Thus the late onset of overt tumours suggests that secondary tumorigenic mutations are necessary for malignancy associated with MLL-AF9 gene fusion and that myeloproliferation provides the pool of cells in which such events can occur. It is shown that fusing the gene encoding β-galactosidase to the mouse Mll gene at exon 8 is sufficient to cause myeloid leukaemia with long latency. Thus Mll truncation alone is sufficient to induce tumours, despite the diversity of the fusion partners. Therefore MLL-mediated leukaemogenesis has at least two components, one is truncation of the MLL coding region and the other is fusion of a partner to provide acceleration of tumour outcome. A mouse model of the Bcr-ABL gene fusion was also made in embryonic stem cells by an homologous recombination knock-in. Only 4 low percentage chimaeras were born from the injection of 272 blastocysts, suggesting that the fusion is embryonic lethal.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available