Analysis of Jagged2 Signaling in Langerahans Cell Histiocytosis
Caroline Hutter MD, PhD
Children’s Cancer Resarch Institute/St. Anna Kinderspital – Vienna, Austria
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Langerhans cell histiocytosis is a disease of unknown origin, characterized by accumulations of histiocytes in various organs. 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 dendritic cells. It is not known yet what JAG2 is doing in LCH, but we think that it could induce circulating dendritic cell progenitors to differentiate into LCH cells and also explain how LCH cells could influence the growth and behavior of certain T cells in LCH lesions called regulatory T cells. This is important, because it could explain why the immune system –which normally should eliminate ‘strange’ cells – cannot get rid of the LCH cells in patients. We therefore plan to investigate how JAG2 can influence this crosstalk of dendritic cells and T cells in an in vitro system. 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.