Identification of the cell of origin in MLL-AF9-associated infant leukaemia

Although blood cancer in infants is rare, it poses a challenging clinical problem. Compared with older children, infants with leukaemia usually present with a more aggressive disease that frequently relapses following treatment. It is known that the disease in infants initiates before birth in a foetal blood cell that has unique properties that contribute to the aggressiveness of the cancer. To be able to develop new treatments that specifically benefit infant patients, it is therefore essential to identify the cell of origin for infant leukaemia, to define its unique properties and to understand how the development of the blood system is affected in infant patients. The aim of this project is to investigate the effect that a mutation commonly found in infant leukaemia, the MLL-AF9 fusion oncogene, has on foetal blood development in a mouse model. Our preliminary data suggest that MLL-AF9 increases blood progenitor output, that it can change the differentiation path of blood progenitors and that it can even cause a block in differentiation, a phenomenon found in many cancers. Furthermore, these effects are very much dependent on the cell type in which MLL-AF9 is expressed. In this project, the student will investigate the effect MLL-AF9 has on foetal blood development in more detail. Importantly, s/he will test if different foetal blood cells that carry the mutation can cause the cancer in a similar manner. Finally, s/he will explore the molecular factors within the cell of origin that assist the mutation in turning it into a cancer cell and interrogate these as potential new drug targets. The project will allow the student to learn state-of-the-art techniques such as RNA-Seq, ATAC-Seq and ChIP-Seq for specific histone modification and they will gain experience in important cancer research technologies such as generation and analysis of in vivo leukaemia models, transformation assays and common functional haematopoietic assays.

For further information please visit: https://www.ed.ac.uk/cancer-centre/study-with-us/cancer-research-uk-phd-programme