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Identification of genes transcriptionally regulated by the E2A-HLF leukaemia-associated fusion protein

Yeung, Jenny; (2005) Identification of genes transcriptionally regulated by the E2A-HLF leukaemia-associated fusion protein. Doctoral thesis , UCL (University College London). Green open access

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Abstract

The E2A-HLF chimaeric transcription factor arises from the t(17;19) translocation in some childhood pro-B acute lymphoblastic leukaemias (ALL). The t(17;19) translocation in childhood ALL is associated with a very poor outcome. Disseminated intravascular coagulopathy and hypercalcaemia at presentation are also associated with the translocation. In vitro experiments have shown that E2A-HLF acts as an anti-apoptotic factor in murine IL-3-dependent cell lines, Baf-3 and FL5.12. A tetracycline-inducible system to express E2A-HLF in Baf-3 cells was established and which confirmed an anti-apoptotic role of E2A-HLF in these cells following IL-3 withdrawal. DNA microarrays were used to identify candidate targets of E2A-HLF that may contribute to its anti-apoptotic and leukaemogenic action. Several candidate target genes were identified and their induction by E2A-HLF was confirmed by Northern blotting analysis and promoter-reporter gene assays. Independent experiments demonstrated that E4BP4, a basic leucine zipper transcription factor related to E2A-HLF, was also a target of E2A-HLF. Experiments assessing the role of E2A-HLF and its target genes on immortalisation and differentiation of primary murine haematopoietic progenitor cells revealed that E2A-HLF functions as a potent oncogene. Expression of E2A-HLF in a retrovirus and infection of bone marrow and foetal liver haematopoietic progenitors cells lead to the immortalisation of myeloid and lymphoid progenitors as shown by colony forming assays and liquid culture. Other workers have demonstrated that the coexpression of both E2A-HLF and BCL-2 was necessary to immortalise lymphoid progenitors. Data presented here shows for the first time that E2A-HLF alone is sufficient to immortalise primary lymphoid progenitors and that co-expression of BCL-2 has a synergistic effect on the immortalisation properties of E2A-HLF.

Type: Thesis (Doctoral)
Title: Identification of genes transcriptionally regulated by the E2A-HLF leukaemia-associated fusion protein
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis. Images identifying individuals have been redacted or partially redacted to protect their identity.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1493573
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