Grants Awarded

The Role of BRAF V600E in the Pathogenesis of Langerhans Cell Histiocytosis

Principal Investigator
Gayane Badalian Very 
Dana-Farber Cancer Institute – Boston, Massachusetts USA

Date of Award
December 2010

Amount of Award

Layperson Summary
Langerhans cell histiocytosis (LCH) is a rare disease that mainly affects children. Cells of the immune system, called Langerhans cells (LCs), accumulate in various organs and causing damage and, in severe cases, leading to death. We have evidence that a specific genetic abnormality called BRAF V600E appears in LCs after birth and we believe that it causes LCH.

In order to prove that this abnormality causes the disease and is not simply associated with it, we will do two things: First, we will test the effects of BRAF V600E on LCs grown in the laboratory. If we are correct, these cells should behave in an abnormal way. Second, we will develop a mouse in which this abnormality occurs in the mouse’s LCs. This will be accomplished by mating a mouse that carries a silent version of the BRAF abnormality in all of its cells with a mouse that carries the instructions for activating the gene in its LCs. This approach is necessary because the mutation can cause a variety of other abnormalities that are irrelevant to our question when it is present in other cell types.

Offspring will then be tested for the presence of an LCH-like disease and for abnormalities in the function of LCs. We will examine organs like skin, lymph nodes, spleen, liver, brain and bone for the presence of LCs and other cells that are found in human patients suffering from LCH. In addition, we will investigate the migration of LCs after mild inflammatory skin challenge and we also will study the isolated LCs outside of the mouse.

Children and adults who suffer from LCH are in need of more-effective treatments. Our project will provide useful tools to examine the effects of novel and potentially-effective drugs, such as targeted therapies against BRAF V600E.

Twelve Month Report