Role of AML1/Runx1 isoforms in development, self-renewal and differentiation of haematopoietic progenitor/stem cells

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The main focus of this research proposal is in the development and regulation of blood stem cells by a gene called AML1/Runx1. Stem cells are one of the main foci of current biology due to their potential to self-replicate and give rise to a variety of mature cells. AML1/Runx1 is critically important for the development of the adult blood system and is frequently involved in the development of human leukaemias. AML1/Runx1 gene produces different forms of the protein which can compete for the influence on other genes which are involved in stem cell development and function as well in the development of leukaemias. We have generated genetically altered embryonic stem (ES) cells and mouse experimental systems which allow AML1/Runx1 gene to be artificially regulated. Regulation of AML1/Runx1 gene is achieved by the use of a modern bi-component tetracycline inducible system. The design of the system enables fine tuning of levels of the AML1/Runx1 protein in cells. The influence of these AML1/Runx1 proteins will be studied in cultured ES cells as well as in developing mouse embryos and in the adult mouse. Two additional genetically modified mice which have fluorescent tagged genes controlled by AML1/Runx1 will also be used in this research to enable accurate identification of cells which express AML1 protein. Better understanding of stem cell regulation and the role of AML1 in this process will have potential implications for the development of protocols for practical regenerative medicine.