Understanding the drivers of APL
The hallmark of acute promyelocytic leukaemia (APL) is the presence of the PML-RARα protein. This results from exchange of material between chromosomes 15 and 17 in a bone marrow cell, triggering the leukaemia. The protein has a damaging effect, disrupting structures in the centre of the bone marrow cells known as “PML nuclear bodies”. Their normal function has been a mystery; however, we have shown that their disruption leads to expansion of more immature cells in the bone marrow and also reduces the efficiency of repair to damaged DNA. We wish to understand the reasons for these effects, which could explain why bone marrow cells acquire additional gene mutations that ultimately lead to the development of leukaemia. Another key question we wish to address is why initial treatment for the same type of leukaemia such as APL can be curative in some patients, while others experience disease relapse or development of a different type of leukaemia. We wish to investigate whether this can be explained by the type of cell in which leukaemias develop and/or the different mutations they contain. In future, these studies may help us to better adapt treatments to the needs of individual patients.