Grant Awarded in 2017

MAP kinase pathway activation, DC development and expression of the LCH phenotype

Principal Investigator
Matthew Collin
Newcastle University
Newcastle Upon Tyne, UK

Date of Award

December 2017

Amount of Award

Layperson Summary

Langerhans Cell Histiocytosis (LCH) is caused by a type of dendritic cell that becomes abnormal due to mutations in its DNA involving genes, such as BRAF, that regulate cell growth and metabolism. Although we know that mutations cause a biochemical activation, we do not understand why abnormal LCH cells appear from this event. In order to investigate this, the first aim is to recreate the BRAF mutation V600E in cell cultures that produce dendritic cells and monocytes. These two types of white blood cell are affected by mutations in patients with LCH but we do not know if one or other is more important in LCH. This in vitro system allows us to study how development is affected by the mutation; specifically, whether there is an expansion of abnormal cells from either dendritic cells or monocytes that begin to resemble LCH cells. The second aim looks in detail at the ability of CD1c+ dendritic cells to form LCH-like cells. We know that these dendritic cells can be split into 3 subpopulations and we aim to find out which has the highest propensity to develop into an LCH-like cell. Finally we will look into the blood of patients to determine if there is a specific expansion of one CD1c+ subset and if so, whether it contains more BRAF mutation than the others. Together these experiments will increase our understanding of how LCH lesions arise by finding out how mutation affects dendritic cell development and looking in more detail at the types of dendritic cells that are involved by mutations. This will help us to realize why specific tissues and organs are targeted by LCH and to gain new insights into the prevention and treatment of painful and debilitating LCH lesions, regardless of the genetic mutation that is present.

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