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The presence of CXCR4(+) CD1a(+) cells at onset of Langerhans cell histiocytosis is associated with a less favorable outcome

Purpose: Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder characterized by tissue accumulating CD1a(+) histiocytes which frequently carry somatic mutations. Irrespective of mutation status, these LCH-cells display constitutively active kinases belonging to the MAPK pathway. We evaluated,...

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Autores principales: Quispel, Willemijn T., Stegehuis-Kamp, Janine A., Blijleven, Laura, Santos, Susy J., Lourda, Magda, van den Bos, Cor, van Halteren, Astrid G.S., Egeler, R. Maarten
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5323006/
https://www.ncbi.nlm.nih.gov/pubmed/28255525
http://dx.doi.org/10.1080/2162402X.2015.1084463
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author Quispel, Willemijn T.
Stegehuis-Kamp, Janine A.
Blijleven, Laura
Santos, Susy J.
Lourda, Magda
van den Bos, Cor
van Halteren, Astrid G.S.
Egeler, R. Maarten
author_facet Quispel, Willemijn T.
Stegehuis-Kamp, Janine A.
Blijleven, Laura
Santos, Susy J.
Lourda, Magda
van den Bos, Cor
van Halteren, Astrid G.S.
Egeler, R. Maarten
author_sort Quispel, Willemijn T.
collection PubMed
description Purpose: Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder characterized by tissue accumulating CD1a(+) histiocytes which frequently carry somatic mutations. Irrespective of mutation status, these LCH-cells display constitutively active kinases belonging to the MAPK pathway. We evaluated, in retrospect, the contribution of individual components of the MAPK-activating and chemotaxis-promoting TNF-CXCR4-CXCL12 axis to LCH manifestation and outcome. Experimental design: CXCR4, CXCL12 and TNF protein expression was immunohistochemically analyzed in 70 LCH-affected biopsies. The presence of CXCR4(+)CD1a(+) cells in peripheral blood (PB) and/or bone marrow (BM) samples was evaluated by flowcytometry in 13 therapy-naive LCH-patients. Results: CXCL12 was detected in 68/70 (97%) biopsies. CXCR4(+)LCH-cells were present in 50/70 (71%) biopsies; their presence was associated with higher levels of intralesional TNF. Circulating CD1a(+)CXCR4(+) cells were detected in 4/13 (31%) therapy-naïve LCH-patients which displayed BRAF(V600E) (2/4), MAP2K1 (1/4) or no (1/4) mutations in their tissues. These CD11c co-expressing CD1a(+)CXCR4(+)cells migrated to CXCL12 in chemotaxis assays. Lesional CXCR4(+)LCH-cells were detected in 18/20 cases who presented with LCH manifestation at multiple sites and in 5/23 (22%) patients who developed additional lesions after initially presenting with a single lesion. The CXCR4 status at onset proved to be an independent risk factor for LCH reactivation in multivariate analysis (odds ratio 10.4, p = 0.034). Conclusions: This study provides the first evidence that CXCR4 is involved in the homing and retention of LCH-cells in CXCL12-expressing tissues and qualifies CXCR4 as a candidate prognostic marker for less favorable disease outcome.
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spelling pubmed-53230062017-03-02 The presence of CXCR4(+) CD1a(+) cells at onset of Langerhans cell histiocytosis is associated with a less favorable outcome Quispel, Willemijn T. Stegehuis-Kamp, Janine A. Blijleven, Laura Santos, Susy J. Lourda, Magda van den Bos, Cor van Halteren, Astrid G.S. Egeler, R. Maarten Oncoimmunology Original Research Purpose: Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder characterized by tissue accumulating CD1a(+) histiocytes which frequently carry somatic mutations. Irrespective of mutation status, these LCH-cells display constitutively active kinases belonging to the MAPK pathway. We evaluated, in retrospect, the contribution of individual components of the MAPK-activating and chemotaxis-promoting TNF-CXCR4-CXCL12 axis to LCH manifestation and outcome. Experimental design: CXCR4, CXCL12 and TNF protein expression was immunohistochemically analyzed in 70 LCH-affected biopsies. The presence of CXCR4(+)CD1a(+) cells in peripheral blood (PB) and/or bone marrow (BM) samples was evaluated by flowcytometry in 13 therapy-naive LCH-patients. Results: CXCL12 was detected in 68/70 (97%) biopsies. CXCR4(+)LCH-cells were present in 50/70 (71%) biopsies; their presence was associated with higher levels of intralesional TNF. Circulating CD1a(+)CXCR4(+) cells were detected in 4/13 (31%) therapy-naïve LCH-patients which displayed BRAF(V600E) (2/4), MAP2K1 (1/4) or no (1/4) mutations in their tissues. These CD11c co-expressing CD1a(+)CXCR4(+)cells migrated to CXCL12 in chemotaxis assays. Lesional CXCR4(+)LCH-cells were detected in 18/20 cases who presented with LCH manifestation at multiple sites and in 5/23 (22%) patients who developed additional lesions after initially presenting with a single lesion. The CXCR4 status at onset proved to be an independent risk factor for LCH reactivation in multivariate analysis (odds ratio 10.4, p = 0.034). Conclusions: This study provides the first evidence that CXCR4 is involved in the homing and retention of LCH-cells in CXCL12-expressing tissues and qualifies CXCR4 as a candidate prognostic marker for less favorable disease outcome. Taylor & Francis 2015-08-31 /pmc/articles/PMC5323006/ /pubmed/28255525 http://dx.doi.org/10.1080/2162402X.2015.1084463 Text en © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.
spellingShingle Original Research
Quispel, Willemijn T.
Stegehuis-Kamp, Janine A.
Blijleven, Laura
Santos, Susy J.
Lourda, Magda
van den Bos, Cor
van Halteren, Astrid G.S.
Egeler, R. Maarten
The presence of CXCR4(+) CD1a(+) cells at onset of Langerhans cell histiocytosis is associated with a less favorable outcome
title The presence of CXCR4(+) CD1a(+) cells at onset of Langerhans cell histiocytosis is associated with a less favorable outcome
title_full The presence of CXCR4(+) CD1a(+) cells at onset of Langerhans cell histiocytosis is associated with a less favorable outcome
title_fullStr The presence of CXCR4(+) CD1a(+) cells at onset of Langerhans cell histiocytosis is associated with a less favorable outcome
title_full_unstemmed The presence of CXCR4(+) CD1a(+) cells at onset of Langerhans cell histiocytosis is associated with a less favorable outcome
title_short The presence of CXCR4(+) CD1a(+) cells at onset of Langerhans cell histiocytosis is associated with a less favorable outcome
title_sort presence of cxcr4(+) cd1a(+) cells at onset of langerhans cell histiocytosis is associated with a less favorable outcome
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5323006/
https://www.ncbi.nlm.nih.gov/pubmed/28255525
http://dx.doi.org/10.1080/2162402X.2015.1084463
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