Modeling Langerhans cell Histiocytosis with patient-derived iPSCs
Dr. Giulio Abagnale
St.Anna Children’s Cancer Research Institute
Date of Award
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Langerhans Cell Histiocytosis (LCH) is the most common histiocytic disorder, characterized by lesions in different tissues where malignant CD1a+/CD207+ cells accumulate. LCH is more common in children and high-risk patient may develop a fulminant form of the disease with high fever, cytopenia and multi-organ failure. LCH is a mysterious illness with features of both cancer and inflammatory disease where little is known of its biology. Our proposal wishes to overcome a major bottleneck in LCH studies: the lack of in vitro models. In fact, LCH cells cannot be cultured ex vivo and no cell lines exist, thus research is often conducted on the already scarce patient samples. This directly impairs progress toward understanding disease origin and finding new treatments.
Using induced Pluripotent Stem Cell (iPSCs) to model LCH in vitro would be a game changer. iPSCs are cells that viaoverexpression of few transcription factors have been reprogrammed back to a pluripotent state similar to the one of embryonicstem cells. iPSCs can self-renew indefinitely and develop into all cell types of the human body. With our project we aim atestablishing a new model to elucidate the molecular mechanisms underlying LCH pathogenesis. Starting from patient blood, we will generate iPSCs harboring the BRAFV600E mutation, the most common genetic alteration in LCH. Since iPSCs can differentiateinto all cell types, we will analyze mutated cells at early and late developmental stages to identify when BRAFV600E becomes adriver of LCH. Moreover, we will investigate whether mutated cells release cytokines causing severe symptoms in LCH and which molecular pathways are affected in mutated cells upon treatment with kinase inhibitors. LCH patients will benefit from this project because it will establish a new model to study the disease in vitro that will be availableto the scientific community.
With this model we will be able to understand the role of the BRAFV600E mutation in causing LCH and how it contributes to its life-threatening symptoms. We will also elucidate the effect of targeted therapy on mutated cells at the molecular level and hopefully identify new potential therapeutic targets to treat LCH more effectively.