Alternative genetic mechanisms of BRAF activation in Langerhans cell histiocytosis
| Autor: | David A. Wheeler, Daniel J. Zinn, Poulikos I. Poulikakos, Oliver A. Hampton, Vijetha Kumar, D. Williams Parsons, Harshal Abhyankar, Rikhia Chakraborty, Carl E. Allen, Nipun Kakkar, Angshumoy Roy, Brooks Scull, Kenneth L. McClain, Miriam Merad, Thomas M. Burke, Karen Phaik Har Lim |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Adult Male Proto-Oncogene Proteins B-raf endocrine system diseases Adolescent Oncogene Proteins Fusion Immunology Biology medicine.disease_cause Biochemistry 03 medical and health sciences 0302 clinical medicine Langerhans cell histiocytosis Protein Domains MAP2K1 medicine Humans skin and connective tissue diseases Child neoplasms Exome sequencing Aged Mutation Myeloid Neoplasia MEK inhibitor Infant Cell Biology Hematology medicine.disease digestive system diseases Enzyme Activation Histiocytosis enzymes and coenzymes (carbohydrates) Histiocytosis Langerhans-Cell 030104 developmental biology Protein kinase domain 030220 oncology & carcinogenesis Child Preschool Cancer research Female |
| Zdroj: | Blood. 128(21) |
| ISSN: | 1528-0020 |
| Popis: | Langerhans cell histiocytosis (LCH) is characterized by inflammatory lesions containing pathologic CD207+ dendritic cells with constitutively activated ERK. Mutually exclusive somatic mutations in MAPK pathway genes have been identified in ∼75% of LCH cases, including recurrent BRAF-V600E and MAP2K1 mutations. To elucidate mechanisms of ERK activation in the remaining 25% of patients, we performed whole-exome sequencing (WES, n = 6), targeted BRAF sequencing (n = 19), and/or whole-transcriptome sequencing (RNA-seq, n = 6) on 24 LCH patient samples lacking BRAF-V600E or MAP2K1 mutations. WES and BRAF sequencing identified in-frame BRAF deletions in the β3-αC loop in 6 lesions. RNA-seq revealed one case with an in-frame FAM73A-BRAF fusion lacking the BRAF autoinhibitory regulatory domain but retaining an intact kinase domain. High levels of phospho-ERK were detected in vitro in cells overexpressing either BRAF fusion or deletion constructs and ex vivo in CD207+ cells from lesions. ERK activation was resistant to BRAF-V600E inhibition, but responsive to both a second-generation BRAF inhibitor and a MEK inhibitor. These results support an emerging model of universal ERK-activating genetic alterations driving pathogenesis in LCH. A personalized approach in which patient-specific alterations are identified may be necessary to maximize benefit from targeted therapies for patients with LCH. |
| Databáze: | OpenAIRE |
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