title: BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups.
abstract: Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207(+) dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207(+) DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. 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. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. 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. 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.
authors.affiliation: Department of Oncological Sciences, 2 Tisch Cancer Institute, and 3 Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029.
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Berres
authors.forename: Karen Phaik Har
authors.initials: KP
authors.lastname: Lim
authors.forename: Tricia
authors.initials: T
authors.lastname: Peters
authors.forename: Jeremy
authors.initials: J
authors.lastname: Price
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takizawa
authors.forename: Hélène
authors.initials: H
authors.lastname: Salmon
authors.forename: Juliana
authors.initials: J
authors.lastname: Idoyaga
authors.forename: Albert
authors.initials: A
authors.lastname: Ruzo
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Lupo
authors.forename: M John
authors.initials: MJ
authors.lastname: Hicks
authors.forename: Albert
authors.initials: A
authors.lastname: Shih
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Simko
authors.forename: Harshal
authors.initials: H
authors.lastname: Abhyankar
authors.forename: Rikhia
authors.initials: R
authors.lastname: Chakraborty
authors.forename: Marylene
authors.initials: M
authors.lastname: Leboeuf
authors.forename: Monique
authors.initials: M
authors.lastname: Beltrão
authors.forename: Sérgio A
authors.initials: SA
authors.lastname: Lira
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Heym
authors.forename: Venetia
authors.initials: V
authors.lastname: Bigley
authors.forename: Matthew
authors.initials: M
authors.lastname: Collin
authors.forename: Markus G
authors.initials: MG
authors.lastname: Manz
authors.forename: Kenneth
authors.initials: K
authors.lastname: McClain
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.forename: Carl E
authors.initials: CE
authors.lastname: Allen
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000954:Antigens, Surface / Q000378:metabolism; D001853:Bone Marrow / Q000473:pathology; D039521:CD11c Antigen / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002648:Child; D002675:Child, Preschool; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006646:Histiocytosis, Langerhans-Cell / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D007223:Infant; D037181:Lectins, C-Type / Q000378:metabolism; D008297:Male; D037241:Mannose-Binding Lectins / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D018952:Antigens, CD34; D000954:Antigens, Surface; D039521:CD11c Antigen; C498497:Cd207 protein, mouse; D000949:Histocompatibility Antigens Class II; D037181:Lectins, C-Type; D037241:Mannose-Binding Lectins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf