Contribution of clonal hematopoiesis to adult-onset hemophagocytic lymphohistiocytosis
Autor: | Jon C. Aster, Florian Perner, Sebastian Birndt, John J Ceremsak, Alison M. Schram, Marie McConkey, Benjamin L. Ebert, Cecilia A. Castellano, Mridul Agrawal, Nancy Berliner, Paul La Rosée, Elizabeth A. Morgan, Sarah Nikiforow, Christopher J. Gibson, German Pihan, Peter Miller, Robert P. Hasserjian, Kaushik Viswanathan, Martin S. Taylor, Jon E. Arnason, Adam S. Sperling |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Adult Male endocrine system Somatic cell Immunology Population Disease Biology Biochemistry Germline Lymphohistiocytosis Hemophagocytic Dioxygenases 03 medical and health sciences Mice Phagocytes Granulocytes and Myelopoiesis 0302 clinical medicine Immune system hemic and lymphatic diseases Proto-Oncogene Proteins medicine Animals Humans Age of Onset education Aged Hemophagocytic lymphohistiocytosis education.field_of_study fungi TLR9 Cell Biology Hematology Middle Aged medicine.disease Mice Mutant Strains DNA-Binding Proteins Haematopoiesis 030104 developmental biology 030220 oncology & carcinogenesis Toll-Like Receptor 9 Mutation Female Clonal Hematopoiesis |
Zdroj: | Blood |
ISSN: | 1528-0020 |
Popis: | Adult-onset hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease of immune hyperactivation. Unlike pediatric HLH, adult HLH is rarely driven by germline genetic variants. Although numerous precipitating etiologies have been identified, the reason that HLH occurs in only a subset of individuals and how other factors contribute to the disease remains unknown. We hypothesized that clonal hematopoiesis (CH), a state in which somatic mutations in blood cells cause an expanded population of mutant hematopoietic cells and drive an aberrant inflammatory state, could contribute to adult-onset HLH. In a highly annotated cohort of older adults with HLH we found that CH was more prevalent than in control cohorts. Using the adult-onset HLH mouse model in which repeated treatments of the TLR9 agonist, ODN1826, was delivered to the mouse, we observed that macrophages carrying mutations in Tet2, one of the most commonly mutated genes in CH, have an enhanced inflammatory response to TLR9 agonism. Finally, mice carrying Tet2 mutations in the hematopoietic compartment (a common model for CH) displayed an exaggerated response to TLR9 agonism, including worse splenomegaly and anemia. Our data suggest that CH is more common in individuals with adult-onset HLH and can contribute to the pathophysiology of this disease. |
Databáze: | OpenAIRE |
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