Grants Awarded

Unraveling the Pathophysiological Role of the BRAFV600E Mutation in Langerhans Cell Histiocytosis (LCH) and its Therapeutical Implications with Murine Models of High-Risk LCH

Principal Investigator
Miriam Merad, MD, PhD
Icahn School of Medicine at Mount Sinai – New York, New York USA

Date of Award
December 2013

Amount of Award

Layperson Summary

Langerhans cell histiocytosis (LCH) is a poorly understood disease that affects mostly children. The disease results from the accumulation of cells called dendritic cells that lead to organ destruction and in some cases to death. The mechanisms that lead to LCH remained poorly understood mainly due to the lack of animal models that are critical for understanding the cause of disease and the development of adapted therapies. Studies from several groups have recently identified an “oncogene” (which means a gene that lead to cancer) called BRAFV600E in more than 50% of LCH lesions in humans. Based on these results, we have generated a new mouse model in which we enforced the expression of the BRAFV600E oncogene specifically in dendritic cells. Strikingly, we found that these mice develop a disease that resembles human LCH. In this application, we ask funding to perform a series of novel experiments to understand the mechanisms that lead to the development of LCH and test the potential of novel therapeutic strategies.

In particular, we would like to explore what the BRAFV600E+ oncogene does to dendritic cells and why BRAFV600E+ dendritic cells accumulate in organs hoping to uncover novel therapeutic agents that can block organ destruction and disease. For example, we found that inhibiting BRAFV600E using a novel therapeutic agent already in use in the clinic for the treatment of other cancers that carry the same mutation, dramatically improved disease outcome in LCH mice. We also discovered that similar to LCH lesions in humans the mouse LCH lesions also contain a large number of another type of immune cells called T lymphocytes. Based on previous research by us and others, we hypothesized that T lymphocytes also contributes to the abnormal accumulation of BRAFV600E+ dendritic cells. Consistent with our hypothesis, we found that T lymphocyte depletion dramatically improved LCH outcome in mice. These are very exciting and promising results and we would like to test whether inhibiting BRAFV600E in addition to eliminating T lymphocytes can synergize for the treatment of LCH. Our goal is to explore in details the potential of these combined strategies for the treatment of LCH and hopefully translate these results for the treatment of LCH patients. Altogether we believe that our application can help transform our understanding of LCH and identify novel therapeutic agents for the treatment of LCH.

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