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In vitro models of TEL/AML1-positive acute lymphoblastic leukaemia

Berks, Richard (2012) In vitro models of TEL/AML1-positive acute lymphoblastic leukaemia. PhD thesis, University of York.

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Acute lymphoblastic leukaemia (ALL) is the most common cancer in children, and is characterised by the proliferation of immature lymphoid cells in the bone marrow. The fusion gene TEL/AML1, generated by the chromosome translocation t(12;21), is the most common single genetic aberration in B-lineage ALL, and is formed from the transcription factors TEL and AML1 (coded for by the genes ETV6 and RUNX1, respectively). However, it is still not clear how the presence of TEL/AML1 causes the development of leukaemia. In addition, the importance of a common secondary mutation in TEL/AML1+ leukaemia, the loss of the untranslocated ETV6 allele, is still subject to debate. The role of TEL/AML1 in malignant haematopoiesis has been previously studied in a variety of models, include in vivo mouse models, in vitro TEL/AML1+ cell lines, and ex vivo patient samples. Each of these models has contributed great amounts to our knowledge about TEL/AML1+ leukaemia; however, each type of model has its disadvantages. Here, a new model is presented which aims to complement these other models, based upon human embryonic stem cells (hESCs) expressing a TEL/AML1 transgene. These transgenic hESCs were shown to be capable of multipotent haematopoietic development, including towards B lymphocytes. The consequence of the loss of TEL in TEL/AML1+ leukaemia is not fully known. Here I provide two insights into this frequent secondary mutation. Firstly, a gene expression microarray revealed the transcriptional role of TEL and illuminated how its loss might contribute to progression of TEL/AML1+ leukaemia. Secondly, the functional role of TEL in proliferation and apoptosis was further investigated, which provided further insight about the clonal evolution of TEL/AML1+ leukaemia. In addition, new discoveries were made of potential partners for heterodimeric transcription factor complexes and targets for TEL repression, which provide new avenues for future studies. Taken together, the data presented in this thesis provides the basis for renewed study into TEL/AML1+ leukaemia which could address remaining questions about the disease.

Item Type: Thesis (PhD)
Keywords: leukaemia hESC TEL AML1 model
Academic Units: The University of York > Biology (York)
Identification Number/EthosID: uk.bl.ethos.564162
Depositing User: Mr Richard Berks
Date Deposited: 10 Jan 2013 14:47
Last Modified: 24 Jul 2018 15:20
URI: http://etheses.whiterose.ac.uk/id/eprint/3160

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