Biomarker identification and preclinical treatment studies in mastocytosis

• Applicant: Dr. Anja Illerhaus
• Subject Area: Dermatology
• Term: from 2016 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 325545886

Mastocytosis is characterized by clonal expansion of mast cells in skin, bone marrow and other tissues. Most patients carry activating mutations of the KIT gene. According to phenotype and extent of mast cell infiltration, mastocytosis is classified into non-advanced categories, such as cutaneous mastocytosis (CM) and indolent systemic mastocytosis (ISM), and advanced categories like systemic mastocytosis with associated hematological non-mast cell lineage disease (SM-AHNMD), aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL). Clinical manifestation of mastocytosis is heterogeneous and can include mast cell mediator symptoms, such as anaphylaxis, diarrhea and pruritus, and dysfunction of various organ systems, such as cytopenia, hepatosplenomegaly, ascites, malabsorption, weight loss and osteoporosis. In patients suffering from advanced mastocytosis the prognosis is poor with a median survival of less than three years. Unfortunately, current treatment options are limited and often not sufficient to control symptoms. However, we and others have recently identified several biomarkers with diagnostic and therapeutic potential (PD-L1, IL-31, bone cytokines).First, the project aims to identify novel biomarkers for mastocytosis to advance our knowledge on the pathogenesis of mastocytosis. This will reveal new molecular targets for the treatment of patients with mastocytosis depending on their disease category. Second, we will investigate the effect of therapeutic agents, targeting different signaling pathways, on mast cell lines in vitro and in vivo, using recently established KIT-transgenic mouse models of mastocytosis (Mx1-Cre/KIT D814Vfl and Mcpt5-Cre/KIT D814Vfl). On the basis of these preclinical treatment studies effective therapeutic strategies, for patients with mastocytosis, can be developed. These studies will certainly lead to more effective and improved patient care.

• DFG Programme: Research Grants