UNDERSTANDING THE ROLE OF C-MYB IN THE PROCESS OF LEUKAEMIC TRANSFORMATION

Diwakar Pattabiraman (2011). UNDERSTANDING THE ROLE OF C-MYB IN THE PROCESS OF LEUKAEMIC TRANSFORMATION PhD Thesis, UQ Diamantina Institute, The University of Queensland.

       
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Author Diwakar Pattabiraman
Thesis Title UNDERSTANDING THE ROLE OF C-MYB IN THE PROCESS OF LEUKAEMIC TRANSFORMATION
School, Centre or Institute UQ Diamantina Institute
Institution The University of Queensland
Publication date 2011-07
Thesis type PhD Thesis
Supervisor Professor Tom Gonda
Associate Professor Andrew Perkins
Associate Professor Nick Saunders
Total pages 242
Total colour pages 24
Total black and white pages 218
Language eng
Subjects 11 Medical and Health Sciences
Abstract/Summary Acute myeloid leukaemia (AML) is a disease of disordered haematopoiesis that results from the acquisition of mutations in haematopoietic stem/progenitors that confer proliferative advantage and impair normal differentiation. The c-myb proto-oncogene and its product (Myb) are key regulators of haematopoietic cell proliferation and differentiation. MYB mRNA is expressed at high levels in most human myeloid and acute lymphoid leukemias and has been shown to be essential for the proliferation of human AML blasts. c-Myb is a sequence-specific DNA-binding transcription factor that coordinates the activation and repression of a large number of target genes. Despite being studied for over three decades, the factors that regulate transformation by c-Myb, and its role in the pathogenesis of human leukaemias are not well understood. There were three main aims of this thesis. First, to explore regulatory mechanisms that control the transforming ability of c-Myb; more specifically its non-covalent interaction with SUMO and its interaction with the transcriptional co-activator CBP/p300. Initially, the identification of a SUMOinteracting motif in the transactivation domain of the c-Myb protein is described that, when bound to SUMO, represses its transactivation and transforming ability. We also carry out studies showing an essential role for interaction of c-Myb with CBP/p300 in the transforming ability of the former. Secondly and following on from the above results, further studies were carried out to explore the role of the c-Myb-CBP/p300 interaction in the development of AML. Using a mouse model, Booreana, which harbours a mutation in the transactivation domain of c-Myb abrogating CBP/p300 interaction, the transforming ability of the oncogenic fusion proteins MLL-ENL and AML1-ETO was assayed. Neither MLL-fusions nor AML1-ETO proteins were able to transform haematopoietic cells from Booreana mice. This was confirmed using another mouse model, Plt6, which harbours a point mutation in p300 interfering with c-Myb interaction. Together, these studies establish an essential role for this interaction in the development of AML. Thirdly, to understand the mechanism by which the oncogenic fusion proteins are able to transform haematopoietic cells from wild-type mice but not Booreana, gene expression profiling was carried out. This has enabled identification of genes that are regulated by AML1-ETO in wild-type mice but not in Booreana mice, providing a platform to define the transcriptional network regulated by the oncogenic fusion protein and the c-Myb-CBP/p300 interaction. This has also been compared to a list of c-Myb target genes identified in a separate expression profiling and ChIP-sequencing experiment, uncovering targets that specifically require interaction with CBP/p300 for their activation or repression. In summary, by carrying out transformation experiments we have uncovered a role for several mechanisms in the transforming ability of c-Myb. Focusing on CBP/p300 binding, we have revealed a novel role for this interaction in the transforming ability of c-Myb, and more importantly, in the development of acute myeloid leukaemia. Transcriptomic analyses have enabled identification of Myb target genes including genes that could be important players in the process of leukaemic transformation, and that may constitute potential therapeutic targets for future intervention.
Keyword haematopoiesis
Leukaemia
Myb
Transformation
SUMO
Target Genes
Additional Notes 25, 41, 49, 103, 104, 111, 113, 117, 119, 121, 123, 129, 133, 135, 137, 139, 141, 143, 149, 151, 153, 170-172

 
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Created: Thu, 08 Dec 2011, 15:10:31 EST by Mr Diwakar Pattabiraman on behalf of Library - Information Access Service