Defining Pathogenic Mechanisms and Therapeutic Opportunities for Langerhans Cell Histiocytosis

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Project summary This is the second competitive renewal of a grant application to identify the pathophysiology and treatment of Langerhans cell histiocytosis (LCH). LCH is a disease characterized by granulomatous lesions with characteristic clonal CD207+ CD1a+ mononuclear phagocytes (MNP) with activating somatic mutations in MAPK pathway genes, most notably BRAFV600E. Clinical presentations are highly variable, from self-resolving single lesions to fatal disseminated disease. Optimal therapeutic strategies for patients with LCH remain a major unmet need. We propose to define the roles of cell of origin, differentiation of cells harboring activating MAPK pathway mutations, and the impact of target tissue on pathogenesis in order to identify and test novel therapeutic strategies to improve outcomes for patients with LCH. The overall goal of expanding on this collaborative research program is to define pathogenic mechanisms and identify and test therapeutic strategies to improve outcomes of patients with LCH. Specific Aim 1: To determine the roles of cell of origin, age, MAPK mutation, and microenvironment (ME) on extent of disease. Building on previous studies, we propose to test the relative role of the cell of origin of the MAPK mutation and hematologic and stroma microenvironment in target tissues in defining extent of disease and clinical phenotype. Specific Aim 2: To identify the contribution of cellular senescence program to LCH pathogenesis and clinical outcomes. The finding that BRAF mutation in early HPC leads to LCH disease led us to explore why and how early HPC expressing BRAFV600E mutations can lead to LCH lesions in the periphery. Strikingly, we found that BRAF mutations in HPC induce a senescence program that enhances mouse and human HPC differentiation into LCH-like cells. We found that BRAF-mutated HPC and LCH cells expressed canonical senescence program including high levels of the cell cycle inhibitor CDKN2a, the antiapoptotic molecule Bcl-xL, increased mTOR activity and senescence associated secretory proteins (SASP) that promote the accumulation of long lived inflammatory LCH-like cells in tissues. Therefore, we will test the contribution of the senescence program to LCH disease outcome. Specific Aim 3: To test the benefit of senolytic drugs in LCH treatment. We will test the therapeutic potential of two senolytic therapies including BH3 mimetics alone and in combination with chemotherapy and MAPK inhibition for LCH.