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Title: Role and functional consequences of PU.1 transcriptional factor loss and mutations in a mouse model of radiation-induced acute myeloid leukaemia
Author: Olme, Carl-Henrik Axel
ISNI:       0000 0004 2713 2468
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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In a mouse model of radiation-induced acute myeloid leukaemia (rAML), the CBA/H strain, copy loss of Sfpi1 is found in up to 90 % of cases. The gene codes for the transcription factor PU.1, an important regulator of haematopoiesis, which acts as a tumour suppressor. Point mutations specifically in the DNA sequence encoding the binding domain of the protein are found at a high frequency, suggesting that the transcription factor has a reduced function in leukaemic blasts. Transgenic CBA/H mice expressing green fluorescent protein (GFP) under the control of the Sfpi1 promoter allowed the use of flow cytometry to, for the first time, study copy loss of Sfpi1 in cases of rAML by analysing the expression levels of GFP. Analysis of mRNA levels of Sfpi1 showed there probably is a different mechanism for leukaemogenesis in cases with point mutations in the sequence encoding the DNA binding domain compared to cases with a wild type Sfpi1, the former potentially through lack of function in the transcription factor PU.1 and the latter through suppression of Sfpi1 gene expression. Fluorescent activated cell sorting was used to isolate immature bone marrow cells (BMC) containing Sfpi1 deletions from previously irradiated mice. The isolated cells were transplanted into myeloablated hosts with some success, although this new approach to study radiation-induced leukaemogenesis needs refinement. A population of immature BMCs was found to be less radiosensitive in the CBA/H strain compared to the C57BL/6 strain, which is not susceptible to rAML. This gave an indication of where the target cell population for the initial leukaemic events may occur. The work in this thesis presents novel ways of studying early events in rAML induction in the CBA/H mouse and gives new insights into the mechanisms of leukaemogenesis in the model.
Supervisor: Porter, Andy ; Badie, Christophe Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral