Grants Awarded

Date of Award
December 2015

Amount of Award
$50,000

Layperson Summary
Langerhans cell histiocytosis (LCH) is a rare disease that may affect any age group, but its most aggressive form is mainly seen in young children. One intriguing feature of LCH is the wide spectrum of clinical manifestations of what is believed to be one disease entity:The clinical course of LCH includes both spontaneous healing of single lesions, as well as a life threatening disease occurring in several organs that requires systemic chemotherapy and, in some cases, haematopoietic stem cell transplantation. Furthermore the question whether LCH is a cancerous or an inflammatory disease is yet unsolved. In this project we aim to enable new, targeted approaches to treatment of LCH by identifying the mechanisms underlying the disease. We have identified the so-called NOTCH signaling pathway as an important clue to the pathogenesis of the disease. The NOTCH pathway is involved in the regulation of normal growth and development, but also active in many different human cancers, for example leukemia. The core pathway consists of a group of transmembrane receptors called NOTCH and ligands called Jagged and Delta. In LCH lesions we found that the NOTCH ligand JAG2 is present at very high levels in LCH cells, but not on other dendriticcells. The exact mechanism how JAG2 influences the outcome and development of LCH is not yet revealed, but our data suggests that it induces circulating dendritic cell progenitors to differentiate into LCH cells. Ultimately, elucidating the role of the NOTCH signaling pathway in LCH might pave the way for new treatment approaches of LCH, especially because clinical trials testing NOTCH inhibitors in different cancers are under way and – if successful – would therefore also be available for the treatment of LCH. Additionally we aim to understand the crosstalk between the NOTCH and the MAPK pathway, which is often deregulated in cancers and was shown to activate the NOTCH pathway. Targeting both NOTCH and MAPK pathway might even enhance treatment outcome and would therefore be our major goal.

Twelve Month Report
With support from the Histiocytosis Association, we have been able to study the Notch pathway in Langerhans Cell Histiocytosis. The NOTCH pathway is not only involved in the regulation of normal growth and development, but also active in many different human cancers, for example leukemia. This pathway consists of a group of transmembrane receptors (called NOTCH) and ligands (called Jagged and Delta). In our previous work, we found that in LCH lesions, NOTCH and its ligand JAG2 are present at very high levels in LCH cells. The exact mechanism of how JAG2 influences the outcome and development of LCH is not yet revealed, but our data suggests it induces circulating dendritic cell progenitors to differentiate into LCH cells. Ultimately, elucidating the role of the NOTCH signaling pathway in LCH might pave the way for new treatment approaches of LCH, especially since clinical trials testing NOTCH inhibitors in different cancers are under way and, if successful, would also be available for the treatment of LCH. To this end, we have tested a NOTCH inhibitor in our cell culture model. There, we incubated dendritic cell progenitors from healthy volunteers together with recombinant JAG2 and after five days in culture, the cells expressed cell surface markers that could also be found on LCH cells. When we treated these cells with a NOTCH inhibitor, which is already in clinical trials, they lost their LCH-like phenotype. Furthermore, we developed a method to transfect these cells which enabled us to directly show the activation of the NOTCH pathway in monocytes by JAG2 via the activation of a reporter signal.

Additionally, we aim to understand the crosstalk between the NOTCH and the MAPK pathways. It has previously been shown that about half of LCH cases have a mutation in a specific gene called BRAF, another 25% in a gene called MAP2K1. Both BRAF and MAP2K1 are important genes in the MAPK pathway. To study the MAPK pathway, we are currently adapting our transfection protocol to be able to express BRAF and the mutated form of BRAF that was found in LCH.

We are very grateful for the support from the Histiocytosis Association