The presence of self-renewing “cancer stem cells” responsible for tumour initiation and maintenance has been well defined in multiple types of solid and haematologic tumours; however, our knowledge of their biology is very limited. While it is believed that leukaemia stem cells (LSC) – like normal haematopoietic stem cells (HSC) – depend on the interaction with a specialized microenvironment or ‘niche’ for their self-renewal and maintenance, the identity and function of this leukaemic niche are essentially unknown. A better understanding of these processes is critical to the development of better therapies, because complete erradication of the tumour requires elimination of LSC. MLL-induced leukaemias represent a group of malignancies with poor clinical outcome, underscoring the need for more effective therapies. In these leukaemias, the presence of self-renewing LSC has been well documented. Here I propose to investigate the contribution of the haematopoietic microenvironment to the development of MLL-induced leukaemias and its role in LSC maintenance and, at the same time, to expand our understanding of the normal HSC microenvironment. We will specifically characterize the role and requirement of nestin+ mesenchymal stem cells (MSC), previously shown to be essential for normal haematopoiesis, as a niche component for LSC. The role of specific extracellular signals (in particular the chemokine SDF), potentially mediating the interaction of MSC with normal and leukaemic HSC, will be investigated. Finally, I propose to study the effects of oestrogens and oestrogen receptor modulation on the proliferation, survival and self-renewal of HSC and their leukaemic counterparts, and their potential role in modifying leukaemic cell chemosensitivity. This project will ultimately attempt to establish the feasibility of targeting the haematopoietic microenvironment as a novel therapeutic approach, and to assess its efficacy in experimental models of MLL-induced leukaemias.
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