Cambridge scientists, in collaboration with colleagues across Europe, have completed the most comprehensive study yet attempted to assess the role of chromatin factors in normal and malignant haematopoiesis, the process of blood formation, in a study published this month in Nature Genetics. The study provides an important breakthrough in explaining the importance of chromatin factors in the formation of blood cells and blood cancers and opens the possibility of entirely new cancer therapies.
Chromatin factors are a group of proteins that help to regulate gene expression through altering the form and structure of chromatin, the mixture of DNA and proteins that form the chromosomes found in the cells of humans and higher organisms. Working together with another set of proteins called transcription factors, they orchestrate the expression of genes from a cell’s DNA that are essential for determining the identity and function of cell types that comprise the organism. Chromatin factors had been thought to be of less importance in this process than transcription factors, however recent studies are establishing them as a crucial dynamic element in the regulation of cells. Their general importance in haematopoiesis, the process by which blood cells are formed, had been established, but their exact role and how their dysregulation can lead to cancer, was still largely unexplained.
The study has provided answers to many of the outstanding questions about the role of chromatin factors in blood formation and beyond. Whereas previous studies had focused on smaller numbers, this group studied 650 chromatin factors, with 60 selected for in-depth analysis of their roles in the formation of the hematopoietic system using technology that allows for the study of individual cells. The depth of the study allowed them to demonstrate great complexity in the way that the expression of genes is regulated, revealing great diversity in the function of related chromatin factors as well as shared roles for unrelated transcription factor-chromatin factor complexes.
Excitingly, the study demonstrated how leukaemia cells corrupt chromatin factor roles, blocking the normal progression of blood cells into mature cell types. Moreover, complexes of transcription factors and chromatin factors were formed that were unique to leukaemia cells. As these complexes are specific to leukaemia and not required for normal blood formation, they can be therapeutically targeted without causing any other harm to the patient, unlike current treatments like chemotherapy that have toxic side-effects. The team are now working on how to target these complexes with new drugs.
Professor Brian Huntly, Head of the University of Cambridge Department of Haematology, who co-led the study, said “This is one of the most exciting projects that I have ever been involved in. We have taken ground-breaking new technology, developed it ourselves and applied it to answer fundamental questions about how blood cells are produced and how blood cancers are formed and maintained.”
Dr David Lara-Astiaso, who spearheaded the study, said “The study has only been possible because of technical advances that we have pioneered in Cambridge and at the University of Navarra and the new computational analysis performed by our collaborators at the University of Salzburg and Relation Therapeutics. They allowed us to study a range of chromatin factors at a depth of analysis that we could never have attempted before. We have plans to develop the technology even further. This is the start of a very exciting period in chromatin factor research.”
Professor Huntly added, “Identifying potential new therapeutic pathways for acute myeloid leukaemia is particularly important. Only around 15% of people diagnosed with the disease survive more than five years.”