The proposed research project plans to investigate the functions of a novel protein, PRDM16 (MEL1), in leukaemogenesis. PRDM16 is a member of the SET domain family of histone lysine methyltransferases and was recently identified by the host laboratory to be rearranged in three cases of acute myeloid leukaemia carrying rare translocations.
In the first case, full length PRDM16 is aberrantly expressed, whereas in the second case, a deleted PRDM16 lacking the SET domain (delPRDM16) is formed. In the third case, an AML1-PRDM16 fusion protein results. We plan to investigate how PRDM16, delPRDM16 and AML1-PRDM16 can give rise to AML. In particular we wish to investigate the importance of the SET domain, how fusion to AML1 alters the function of PRDM16, and whether AML1-PRDM16 can function in a similar way to AML1-ETO.
In vitro assays will initially be performed to investigate the biological phenotypes induced by each protein (PRDM16, delPRDM16, AML1-PRDM16 or AML1-ETO). The proteins will be over-expressed in murine haematopoietic progenitor cells (lin- cells) and will be assessed for their ability to block myeloid differentiation, increase survival upon genotoxic stress, and increase self-renewal.
In vivo assays will also be carried out to test the ability of the proteins to induce leukaemia in mice. In order to identify target genes commonly regulated by AML1-PRDM16 and AML1-ETO, Affymetrix gene expression microarrays will be employed. The proposed project will yield many important insights into the functions of PRDM16 and how its aberrant expression contributes to leukaemia.
The researcher has a background in mapping fusion genes in cancer and will therefore greatly expand her repertoire of laboratory skills by performing functional studies on a novel protein. The project will not only allow the researcher to become a highly skilled and independent scientist, but will make an important contribution to European cancer research.
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