Timothy Barrow, PhD
Lecturer, Life Sciences
University of Essex
Research
Developing Novel Markers of Minimal Residual Disease for Chronic Lymphocytic Leukemia
Summary
Chronic lymphocytic leukemia (CLL) is the most common adult form of leukemia. While traditionally considered incurable, new drugs are coming into the clinic that offer hope of extended remission or even cure. In order to monitor how patients respond to treatment and predict risk of relapse, we need sensitive laboratory assays that measure the number of leukemic cells that remain in the blood, referred to as minimal residual disease (MRD). Genetic assays that detect abnormalities in DNA are routinely used for other forms of leukemia but have not been developed for CLL because suitable targets have not been found. I have identified changes in the chemical modification of DNA, referred to as DNA methylation, that are present in more than 90% of CLL patients. To determine whether these could be used for measuring MRD, I will address two questions. Firstly, I will determine whether the loss of DNA methylation is caused by mutations that prevent the DNA from being methylated. This is important because detecting mutations is simpler and cheaper to do. Secondly, I will determine whether these changes are only present in leukemic cells in the patient’s blood, as early genetic changes leading to cancer can sometimes be seen in normal cells as well. This project will determine whether the changes I identified in CLL patients can be used to develop new assays for measuring MRD, which would benefit patients by improving the monitoring of their response to treatment and risk of relapse.
Impact
This funding from Leukemia Research Foundation has enabled me to make progress towards the development of novel assays for assessment of MRD in CLL patients. This is an area of clinical need, as there is currently a lack of sensitive genetic MRD assays for CLL that can inform treatment for patients and improve outcomes.
Flow cytometry is ten-times less sensitive than most genetic assays, and not all clinical laboratories within the National Health Service of the UK have the required capability to perform such work. The only genetic MRD tests available for CLL are expensive, complex and require baseline samples for comparison. This research is therefore meeting a clinical need. While my work in this area is ongoing, the results from this project will be built upon and the assays taken forward for further examination. We will seek to further refine the assays to improve their specificity, and to apply these to samples from CLL biobanks within the UK in order to examine their clinical utility in predicting patient outcomes. To achieve these aims, the results of this project will be used to support applications for funding from new sources to expand our examination of these loci as novel clinical biomarkers.
The results from the work still in progress will also provide mechanistic insight into the origins of the observed epigenetic changes. They will inform our understanding of how early epigenetic changes can occur during the development of CLL and how they are implicated in its pathogenesis. Furthermore, if our hypothesis is proven to be correct then this may have implications for other malignancies. We will use the results from this project to support grant applications for funding to facilitate work examining the biological mechanisms underpinning the disruption of the epigenome in CLL development. As a highly novel hypothesis, we believe the findings of such studies will be of great interest to those working within the field of blood cancer research, and also to those working on epigenetic changes in other malignancies.
Leukemia Research Foundation grant
$96K awarded in 2022
Disease focus
Chronic lymphocytic leukemia (CLL)
Research focus
Relapse prevention (minimal residual disease)