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Dr Owen Williams
Molecular Haematology & Cancer Biology Unit
UCL Institute of Child Health
30 Guilford Street
London
WC1N 1EH
Appointment
  • Reader in Cancer Biology
  • ICH Development Bio & Cancer Prog
  • UCL GOS Institute of Child Health
  • Faculty of Pop Health Sciences
Research Themes
Research Summary

Haematopoiesis and Leukaemia Group
 
Group Members
 
Jasper de Boer (Post Doctoral Fellow)
Vanessa Walf-Vorderwulbecke (Post Doctoral Fellow)
Maurizio Mangolini (PhD Student)
Lu Zhao (PhD Student)
Aishwarya Sundaresh (PhD Student)
 
Mechanisms of oncogenesis in infant and childhood leukaemia

 
Chromosomal translocations are frequent in infant and childhood leukaemia. These translocations often result in the generation of unique fusion genes. We are investigating the function of fusion genes that are commonly associated with infant and childhood acute lymphoblastic leukaemia (ALL) and infant acute myeloid leukaemia (AML).
 
MLL Fusions
 
Translocations involving the Mixed Lineage Leukaemia (MLL) gene on chromosome band 11q23 are most prevalent in infant leukaemia where they comprise 80% of ALL and 60% of AML cases. Infant leukaemias bearing the MLL translocations have a particularly poor prognosis. MLL-ENL and MLL-AF9 are two of the most frequent fusion genes produced by these translocations. We have generated an in vitro model for conditional expression of MLL-ENL/AF9 in primary haematopoietic progenitor cells. Using this model we have demonstrated that immortalized myeloid cell lines are dependent on continued MLL-fusion expression for their survival and proliferation. We have also shown that the fusion proteins may contribute to leukaemogenesis by aberrantly maintaining the expression of particular Hox genes, a family of transcription factors involved in haematopoietic differentiation. We have also used these conditionally immortalized cells to induce AML in vivo. These leukaemias were found to have acquired additional genetic changes and chromosomal aberrations and induced secondary leukaemias with accelerated latency. However, we found that even established leukaemia could be completely eradicated by silencing of MLL-fusion expression. This suggests that leukaemic cells remain absolutely dependent on transcriptional networks established by MLL-fusions, despite acquisition of secondary mutations, and demonstrates the therapeutic efficacy of targeting MLL-fusion activity.
 
TEL-AML1
 
The t(12;21)(p13;q22) translocation is present in up to 25% of children with pre-B cell ALL. This translocation results in the fusion of the AML1 (RUNX1) with the TEL (ETV6) gene and generates a TEL-AML1 fusion transcription factor. We have used retroviral transduction of primary haematopoietic progenitor cells to demonstrate that TEL-AML1 promotes B cell differentiation in vitro and haematopoietic reconstitution in vivo. We have also demonstrated that although TEL-AML1 immortalises pre-B cells in vitro, it is not sufficient to induce leukaemia in vivo. These results are consistent with the hypothesis that TEL-AML1 expression produces pre-leukaemic cells which are predisposed to generate overt leukaemia after the acquisition of secondary mutations. We have generated a panel of deletion mutants, in order to determine which protein domains were required for TEL-AML1 activity. Experiments with these mutants established a number of domains critical for the promotion of B cell development by TEL-AML1. These experiments indicate that TEL-AML1 functions as an aberrant transcription factor, potentially deregulating the expression of AML1 target genes.
 
 
We are currently involved in identifying transcriptional targets of both the MLL-ENL/AF9 and TEL-AML1 fusions using Affymetrix GeneChip global expression analysis. These analyses have identified a  number of signalling pathways that are deregulated by both classes of oncogenes and that represent candidates for novel therapeutic interventions.

Academic Background
1991 PhD Doctor of Philosophy – Immunology University College London
1987 BSc Hons Bachelor of Science (Honours) – Biochemistry University College London
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