The first descriptions of LCH, including Hand-Schüller-Christian disease and Letter-Siwe disease, were based on anatomical location and extent of the lesions ( Arceci, 1999). LCH has pleotropic clinical presentations ranging from single lesions cured by curettage to potentially fatal multi-system disease. Langerhans cell histiocytosis (LCH) is characterized by inflammatory lesions that include pathological langerin + DCs. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c + and CD14 + fractions and in bone marrow (BM) CD34 + hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207 + DC in low-risk LCH patients. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207 + DCs. Recurrent BRAF-V600E mutations have been reported in LCH. “Transcription imparts architecture, function, and logic to enhancer units.” bioRxiv (2019): 818849.Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207 + dendritic cells (DCs) in inflammatory lesions. “Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal.” Cell Stem Cell,, 10.1016/j.stem.2020.04.010. “The Mitochondrial Transacylase, Tafazzin, Regulates AML Stemness by Modulating Intracellular Levels of Phospholipids.” Cell Stem Cell, vol. “Cholecalciterol Cholesterol Emulsion Attenuates Experimental Autoimmune Myocarditis in Mice via Inhibition of the Pyroptosis Signaling Pathway.” Biochemical and Biophysical Research Communications, vol. “BioBits TM Explorer: A Modular Synthetic Biology Education Kit.” Science Advances, vol.
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