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Vemurafenib acts as a molecular on-off switch governing systemic inflammation in Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a neoplasm marked by the accumulation of CD1A(+)CD207(+) cells. It is most commonly driven by a somatic, activating mutation in the BRAF serine-threonine kinase (BRAF(V600E)). Multisystem disease with risk-organ involvement requires myelotoxic chemotherapy, mak...

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Autores principales: Eder, Sebastian K., Schwentner, Raphaela, Ben Soussia, Philipp, Abagnale, Giulio, Attarbaschi, Andishe, Minkov, Milen, Halbritter, Florian, Hutter, Caroline
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Hematology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8945316/
https://www.ncbi.nlm.nih.gov/pubmed/34619771
http://dx.doi.org/10.1182/bloodadvances.2021005442
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author Eder, Sebastian K.
Schwentner, Raphaela
Ben Soussia, Philipp
Abagnale, Giulio
Attarbaschi, Andishe
Minkov, Milen
Halbritter, Florian
Hutter, Caroline
author_facet Eder, Sebastian K.
Schwentner, Raphaela
Ben Soussia, Philipp
Abagnale, Giulio
Attarbaschi, Andishe
Minkov, Milen
Halbritter, Florian
Hutter, Caroline
author_sort Eder, Sebastian K.
collection PubMed
description Langerhans cell histiocytosis (LCH) is a neoplasm marked by the accumulation of CD1A(+)CD207(+) cells. It is most commonly driven by a somatic, activating mutation in the BRAF serine-threonine kinase (BRAF(V600E)). Multisystem disease with risk-organ involvement requires myelotoxic chemotherapy, making BRAF-inhibitors an attractive treatment option. Here, we present a comprehensive analysis of the course of an LCH patient treated with the combination of vemurafenib and salvage chemotherapy who achieved sustained clinical and molecular remission. We show that there is no relationship between peripheral blood BRAF(V600E) levels and clinical presentation during treatment with vemurafenib, but that vemurafenib leads to a fast, efficient, but reversible inhibition of clinical manifestations of systemic inflammation. In line, serum levels of inflammatory cytokines exactly mirror vemurafenib administration. Genotyping analysis identified the BRAF(V600E) mutation in multiple hematopoietic cell types, including NK cells and granulocytes. Single-cell transcriptome analyses of peripheral blood and bone marrow cells at time of diagnosis and during treatment indicate that RAF-inhibition abrogates the expression of inflammatory cytokines previously implicated in LCH such as IL1B and CXCL8. Together, our data suggest that while the CD1A(+)CD207(+) histiocytes are the hallmark of LCH, other BRAF-mutated cell populations may contribute significantly to morbidity in patients with multisystem LCH.
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spelling pubmed-89453162022-03-28 Vemurafenib acts as a molecular on-off switch governing systemic inflammation in Langerhans cell histiocytosis Eder, Sebastian K. Schwentner, Raphaela Ben Soussia, Philipp Abagnale, Giulio Attarbaschi, Andishe Minkov, Milen Halbritter, Florian Hutter, Caroline Blood Adv Stimulus Report Langerhans cell histiocytosis (LCH) is a neoplasm marked by the accumulation of CD1A(+)CD207(+) cells. It is most commonly driven by a somatic, activating mutation in the BRAF serine-threonine kinase (BRAF(V600E)). Multisystem disease with risk-organ involvement requires myelotoxic chemotherapy, making BRAF-inhibitors an attractive treatment option. Here, we present a comprehensive analysis of the course of an LCH patient treated with the combination of vemurafenib and salvage chemotherapy who achieved sustained clinical and molecular remission. We show that there is no relationship between peripheral blood BRAF(V600E) levels and clinical presentation during treatment with vemurafenib, but that vemurafenib leads to a fast, efficient, but reversible inhibition of clinical manifestations of systemic inflammation. In line, serum levels of inflammatory cytokines exactly mirror vemurafenib administration. Genotyping analysis identified the BRAF(V600E) mutation in multiple hematopoietic cell types, including NK cells and granulocytes. Single-cell transcriptome analyses of peripheral blood and bone marrow cells at time of diagnosis and during treatment indicate that RAF-inhibition abrogates the expression of inflammatory cytokines previously implicated in LCH such as IL1B and CXCL8. Together, our data suggest that while the CD1A(+)CD207(+) histiocytes are the hallmark of LCH, other BRAF-mutated cell populations may contribute significantly to morbidity in patients with multisystem LCH. American Society of Hematology 2022-02-03 /pmc/articles/PMC8945316/ /pubmed/34619771 http://dx.doi.org/10.1182/bloodadvances.2021005442 Text en © 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
spellingShingle Stimulus Report
Eder, Sebastian K.
Schwentner, Raphaela
Ben Soussia, Philipp
Abagnale, Giulio
Attarbaschi, Andishe
Minkov, Milen
Halbritter, Florian
Hutter, Caroline
Vemurafenib acts as a molecular on-off switch governing systemic inflammation in Langerhans cell histiocytosis
title Vemurafenib acts as a molecular on-off switch governing systemic inflammation in Langerhans cell histiocytosis
title_full Vemurafenib acts as a molecular on-off switch governing systemic inflammation in Langerhans cell histiocytosis
title_fullStr Vemurafenib acts as a molecular on-off switch governing systemic inflammation in Langerhans cell histiocytosis
title_full_unstemmed Vemurafenib acts as a molecular on-off switch governing systemic inflammation in Langerhans cell histiocytosis
title_short Vemurafenib acts as a molecular on-off switch governing systemic inflammation in Langerhans cell histiocytosis
title_sort vemurafenib acts as a molecular on-off switch governing systemic inflammation in langerhans cell histiocytosis
topic Stimulus Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8945316/
https://www.ncbi.nlm.nih.gov/pubmed/34619771
http://dx.doi.org/10.1182/bloodadvances.2021005442
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