TEMPLe · Translating Epigenetic Memory into Personalized Prognostic Solutions for Chronic Lymphocytic Leukemia

Predicting the future clinical behaviour of a patient’s cancer remains a major scientific and clinical challenge. Chronic Lymphocytic Leukaemia (CLL), the most common leukaemia in the Western world, exhibits a broad range of clinical behaviours. The disease begins with a premalignant state that can later progress into an asymptomatic, progressive and highly aggressive form with a poor prognosis. Predicting the risk and timing of progression is a major unmet clinical need in CLL. Through our ERC-SyG grant BCLLatlas and previous studies, we have revealed that DNA methylation plays a key role in cellular identity and memory. These observations indicate that: 1) neoplastic cells carry epigenetic imprints of their cellular origin allowing the distinction of epigenetic subtypes; 2) a mitotic clock traces the proliferative history of cancer cells; and 3) stochastically fluctuating DNA methylation serves as a molecular barcode to track cancer evolutionary dynamics. In CLL, all three nuances of epigenetic memory have a profound and independent prognostic impact. Can these independent prognostic variables be integrated into a single score? In TEMPLe, we propose to leverage the rich information on cellular memory that is encoded within the cancer epigenome by integrating these three variables and generating personalized risk-scores to predict future clinical outcomes of CLL. We will make significant steps towards developing solutions suitable for clinical translation by 1) generating a user-friendly digital platform for risk prediction and prognosis assessment, 2) defining the intellectual property (IP) strategy and best exploitation route in close collaboration with the Technology Transfer Office and IP experts. In the medium term this will improve the clinical management of CLL, and in the long term, this strategy could be applied to other cancers, providing a valuable global asset in precision oncology.