Cell competition as a tumour suppressor in leukaemia

Leukaemia is a devastating disease that, despite advances in treatment, still carries a poor prognosis, and as such the disease represents a huge burden on the health care system. Like all cancers, leukaemia evolves through various pre-cancerous conditions before emerging as a fully malignant disease. Along the way, many tumour suppressive systems that the organism has in place must fail.

One such mechanism that has recently come to light is cell competition. The term “cell competition” describes the phenomenon whereby a community of cells have the ability to sense each others’ fitness, and actively eliminates those deemed less fit by their neighbours. First observed in Drosophila, it has subsequently been studied primarily in cell culture systems, including mammalian cells.

Recent in vivo studies have revealed a role for cell competition in tumour suppression. This has been documented in T cell leukaemia (T-ALL) in mice, where an engineered deficiency in normal cell competition is sufficient to induce a leukemic phenotype. Because cell competition is a tumour suppression phenomenon that occurs in advance of the onset of leukaemia, we need pre-leukemic models to study it.

We work with a mouse model, the NUP98-HOXD13 transgenic mouse, which is a well-established model of pre-leukaemia. This project will take advantage of this model to investigate the phenomenon of cell competition in the pre-leukemic phases of both AML and T-ALL. We have observed this process occurring in this model, and identified one key gene, with more to be discovered. The overarching aim of the project is to better understand cell competition in normal and disease haematopoiesis, using techniques such as genetic manipulation of the mouse model, advanced imaging techniques, flow cytometry, and single-cell gene expression profiling.