Title |
Alternative genetic mechanisms of BRAF activation in Langerhans cell histiocytosis
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Published in |
Blood, October 2016
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DOI | 10.1182/blood-2016-08-733790 |
Pubmed ID | |
Authors |
Rikhia Chakraborty, Thomas M Burke, Oliver A Hampton, Daniel J Zinn, Karen Phaik Har Lim, Harshal Abhyankar, Brooks Scull, Vijetha Kumar, Nipun Kakkar, David A Wheeler, Angshumoy Roy, Poulikos I Poulikakos, Miriam Merad, Kenneth L McClain, D Williams Parsons, Carl E Allen |
Abstract |
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 approximately 75% of LCH cases, including recurrent BRAF-V600E and MAP2K1 mutations. In order 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 LCH patients. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 2 | 25% |
Canada | 1 | 13% |
Unknown | 5 | 63% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 5 | 63% |
Scientists | 1 | 13% |
Science communicators (journalists, bloggers, editors) | 1 | 13% |
Practitioners (doctors, other healthcare professionals) | 1 | 13% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 78 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 14 | 18% |
Researcher | 12 | 15% |
Other | 11 | 14% |
Student > Master | 7 | 9% |
Student > Postgraduate | 5 | 6% |
Other | 17 | 22% |
Unknown | 12 | 15% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 29 | 37% |
Biochemistry, Genetics and Molecular Biology | 12 | 15% |
Agricultural and Biological Sciences | 7 | 9% |
Immunology and Microbiology | 6 | 8% |
Chemistry | 2 | 3% |
Other | 5 | 6% |
Unknown | 17 | 22% |