The transcription factor SOX7 plays a central role in the development of the cardio-vascular system. Its expression is tightly regulated at the onset of blood and endothelium specification and its sustained expression in immature blood cells blocks differentiation and promotes proliferation, leading to the accumulation of immature blood cells. This striking effect on early blood specification led to the hypothesis that the mis-expression of Sox7 may confer a proliferative or survival advantage to adult cells and that Sox7 might be implicated in the emergence or maintenance of leukaemia initiating cells. Analysis of SOX7 expression in multiple cases of human leukaemia revealed that this transcription factor was significantly and specifically expressed in B-Cell Acute Lymphoblastic Leukaemia (B-ALL). Based on this observation, I first investigated in a mouse model the consequences of Sox7-enforced expression on the homeostasis of adult haematopoiesis and during the B cell differentiation. In vitro, Sox7-enforced expression impaired the differentiation of B cells and induced the proliferation of immature progenitor cells. In vivo, Sox7-enforced expression also blocked B cell differentiation, caused splenic enlargement and induced the accumulation of fibrotic fibres in the bone marrow, all signs of a pre-leukaemic stage. To investigate the role for SOX7 in the formation and maintenance of human leukaemia, I knocked-down the expression of SOX7 in B-ALL cell lines. This resulted in a significant decrease in the proliferation of these B-ALL cells in vitro. Upon engraftment in vivo, I observed that the down-regulated expression of SOX7 induced a significant increase in survival rate.Altogether, the findings presented in this thesis demonstrate for the first time the correlation between SOX7 expression and the B-ALL and the maintenance of immature progenitor cells by Sox7-enforced expression.
|Date of Award||1 Aug 2015|
- The University of Manchester
|Supervisor||Valerie Kouskoff (Supervisor)|