Professor Brian Huntly’s team at the University of Cambridge Department of Haematology has shown that loss of CREBBP (CREB Binding Protein), a gene frequently mutated in human lymphomas, leads to the development of a pre-malignant stem cell population that evolves over time to ultimately give rise to full blown lymphoma.
They have shown that the timing of CREBBP loss is important in determining the development of lymphoma. Mice who lost the CREBBP gene early in haematopoiesis developed white blood cell (lymphocyte) precursors with enhanced self-renewal properties and inadequate responses to DNA damage, resulting in the development of other mutations and a significant increase in lymphoma development. Conversely, loss of CREBBP at a later time point, once the stem cells had committed to becoming lymphocytes, resulted in a weakening of lymphoma development.
Professor Huntly: “Loss of CREBBP results in a pre-malignant stem cell population that replicates excessively and does not respond appropriately to DNA damage. This seems to create a perfect storm for the subsequent acquisition of DNA mutations that lead to the development of lymphoma. To our knowledge, this research is the first to demonstrate the existence of a population of dysfunctional pre-malignant stem cells relating to mature lymphoid malignancy, an important finding in the search for effective therapeutics.”
Professor Huntly’s group will now investigate how loss of the CREBBP gene leads to alterations in the DNA damage pathway and whether these can be targeted therapeutically in lymphoma patients.