Assessment of an in vitro acute lymphoblastic leukaemia model for high-throughput arrayed CRISPR screening

In collaboration with the Milner Therapeutics Institute, this project aims to further develop a human cell-based model for use in medium- and high-throughput CRISPR screens to replace some mouse studies in leukaemia research.

Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer with over 500 cases diagnosed in the UK each year. Treatment can have severe side effects and is not always successful, which has been attributed to the interaction between bone marrow and leukaemia cells. Mouse models have been the mainstay to study these interactions and in the development of therapies that target this crosstalk, however physiological differences between human and mouse bone marrow has contributed to the lack of successful therapies for this disease. There is an urgent need to develop more relevant models to better understand this bone marrow-leukaemia cell crosstalk. Through an NC3Rs fellowship, Dr Deepali Pal established a human cell-based model using patient-derived leukaemia cells cultured on bone marrow mesenchymal stem cells to study the interactions between these cell types. Using this approach, Deepali replaced 73% (2680 mice) of the mice she would have used in carrying out studies to assess the impact of 67 drugs on bone marrow-leukaemia cell crosstalk. Working with the Milner Therapeutics Institute, Deepali will now adapt the cell model to CRISPR screens to demonstrate the utility of using these methods to find new gene pathways related to ALL and bone marrow cell interaction and how these contribute to drug resistance and leukaemia cell dormancy.