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Title: In vivo analysis of the ETV6-CBFA2 fusion gene
Author: Hart, Stephen Michael
ISNI:       0000 0001 3541 4201
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2001
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The ETV6-CBFA2 (TEL-AML1) fusion gene arises from the chromosomal translocation, t(12;21)(p13;q22) which occurs in approximately 30% of childhood B-cell acute lymphoblastic leukaemia. The role of the fusion gene in leukaemogenesis was investigated by using a DNA construct containing the murine Etv6 exon 5 fused in frame to human CBFA2 (exon 2-8) to mimic the ETV6-CBFA2 fusion identified in human acute lymphoblastic leukaemia. This DNA-targeting construct was introduced by homologous recombination into mouse embryonic stem cells and the fusion gene shown to be transcribed under the control of endogenous Etv6 elements. High level chimeras were generated by blastocyst injection of targeted embryonic stem cells. The chimeras were subsequently crossed to generate offspring heterozygous for the Etv6-CBFA2 mutation. To date, neither the chimeric animals (at 14.5 months) nor the heterozygous offspring (at 10 months) have demonstrated any overt phenotypic evidence of leukaemia. However, mice homozygous for the Etv6-CBFA2 mutation died between dE10.5-11.5. The phenotype of these embryos was similar to that described in the Etv6 knock-out model. Our study demonstrates that the Etv6-CBFA2 fusion gene resulting from the t(12;21) translocation is not, by itself, oncogenic and we postulate that further genetic events are required for the development of leukaemia. Furthermore, the lethal phenotype observed in the mice carrying the homozygous disruption of the Etv6 gene is likely to be due to a lack of the Etv6 DNA binding domain.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available