Ayton, Paul Michael; (1998) The role of mixed lineage leukaemia oncogene during mammalian development. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The MLL gene has been recently identified as a common target for multiple chromosomal translocations, as well as more infrequent inversions, duplications and deletions that are associated with acute lymphoid and myeloid leukaemogenesis. The primary structure of the MLL protein contains numerous putative functional domains including similarity to Drosophila trx, suggesting it to be a transcriptional regulator. The function of MLL during development or the mechanisms by which mutant MLL proteins facilitate haematopoietic transformation are currently not known. The aims of this thesis were to investigate both the function of MLL during development in vivo and to address potential mechanisms of MLL mediated oncogenesis. The genomic locus of the murine homologue of MLL was isolated and its structural organisation defined. An isogenic gene targeting vector was introduced into ES cells which, after homologous recombination had taken place, generated a mutation that specifically truncated the Mll reading frame at the position where the gene is consistently fused to a variety of leukaemia translocation partner genes. Targeted ES cells were used to generate chimeric mice which transmitted the mutation through their germline. Mll-/- animals did not complete gestation, suggesting that target genes downstream of Mll control critical steps during embryogenesis. Adult Mll+/- mice were analysed to determine whether haploinsufficiency contributed to haematopoietic transformation. Mll+/- mice exhibited low penetrant and variably expressive defects to the development of immature pre B, CDS ISP thymocyte and granulocytic populations, although terminal maturation of all haematopoietic lineages was observed. The combination of Mll haploinsufficiency and loss of p53 function did not disturb lymphopoiesis or accelerate the onset of p53 deficient lymphomagenesis, but did generate novel immature thymic lymphomas with full penetrance. These tumours consisted of dual populations that included variable proportions of CDS ISP and DP thymocytes, suggesting that loss of p53 function accentuates the effects of MU haploinsufficiency upon thymocyte development. As Mll+/- mice did not develop leukaemia over an 18 month period, it is concluded that Mll haploinsufficiency alone is not sufficient for transformation. These results support a model whereby MLL mutant proteins may transform haematopoietic progenitor populations by a dominant gain of function mechanism that requires the production of fusion proteins with a requirement for contributions from both MLL and partner proteins.

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