Hirako, Mayu; (2003) Homeobox gene expression in normal haematopoiesis and leukaemogenesis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

MLL (Mixed-Lineage or Myeloid-Lymphoid Leukaemia), the mammalian homologue of the Drosophila trithorax gene, is a gene located on chromosome band 11q23 that is frequently rearranged in myeloid and lymphoblastic leukaemias. The mechanism by which MLL rearrangements lead to leukaemia is still unknown. One potential mechanism by which MLL rearrangements give rise to leukaemia is by deregulation of its target genes. Therefore, the purpose of this project was to investigate the expression of MLL target genes in haematopoiesis and to determine if their deregulation is associated with leukaemogenesis. Two putative target genes of MLL were selected for this study: PITX2 (also known as ARP1 <ALL-1/MLL responsive protein 1>, Rieg, Otlx or Brx1) and HOXA7. The bicoid-related homeobox gene PITX2 was initially identified as the causative gene for the autosomal dominant human disorder, Rieger syndrome. It is also involved in the formation of left-right asymmetry and anterior structures during embryogenesis. Recently, Pitx2 was isolated by differential display as a gene that is down-regulated in MLL knockout embryonic stem cells. To investigate if PITX2 is involved in haematopoiesis, the expression pattern in normal and leukaemic cells was studied by RT-PCR and northern blotting. The results indicate that PITX2 is expressed in normal haematopoietic cells but suggest that it is not regulated by MLL and is not deregulated in leukaemic cells. HOXA7 up-regulation is associated with a poor prognosis in patients with acute myeloid leukaemia. To study the potential role of HOXA7 in myeloid differentiation the U937 cell line was used. U937 cells are promonocytic cells that can be induced to differentiate into a more mature macrophage-like phenotype in vitro by addition of PMA. The Tet-Off system was used to overexpress HOXA7 during differentiation and markers of proliferation and differentiation were analysed. No differences in proliferation were observed. However, there was a marked reduction in the number of CD11b-expressing cells and adherent cells. Both are markers of differentiation. The results suggest that de-regulation of HOXA7, but not PITX2, could contribute to a leukaemic phenotype.

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