Grants Awarded

Principal Investigator:
Paul Milne
Haematopoesis and Immunity Lab, Newcastle University,
Newcastle upon Tyne,UK

Date of Award:
December 2024

Amount of Award:
$50,000

Layperson Summary:

Langerhans cell histiocytosis (LCH) and Erdheim Chester disease (ECO) are caused by a mutation, most commonly BRAFV600E, that occurs at some point in the development of white blood cells. These cells eventually mature into histiocytes in the lesions that cause disease around the body. A major puzzle that is relevant to every patient is when did this mutation occur? In this project we are using technique called phylogenetic mapping to ‘date stamp’ BRAFV600E and track its progress over time. We take a pool of single blood and lesional cells and map their family tree by the tiny similarities and differences that have arisen in their DNA as cells divide. This allows us to go backwards in time over many years to the origin of BRAFV600E. In the proposal we will pilot a new technique call ‘PTA’ to allow us to get the DNA from single cells to make the map. What will phylogenetic mapping tell us? In infant LCH it will tell us whether BRAFV600E occurs before birth, early enough to spread to multiple organs, or later, when the blood develops. This is critical for solving the problem of neurodegeneration. It is possible that the brain histiocytes are affected by mutation as the brain develops in the embryo, a long time before the onset of LCH. Alternatively, blood cells might bring the mutation into the brain later, when a child becomes ill with LCH. These two possibilities are very different and deciding between them is critical for developing the best approach to preventing neurodegeneration. In older patients with LCH or ECO, the research will tell us how long the disease has been developing before symptoms occurred and whether there are any other mutations or genetic aberrations involved. In older patients, it is common to find small clones of blood cells carrying mutations. It is likely that these clones interact with BRAFV600E to influence where the disease goes, how severe it is and whether it develops into LCH, or ECO. In summary, phylogenetic mapping provides a ‘life history’ of histiocytosis of each patient that offers the chance of better personalized therapy.