title: The presence of CXCR4+CD1a+cells at onset of Langerhans cell histiocytosis is associated with a less favorable outcome.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 BRAFV600E(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.
authors.affiliation: Immunology Laboratory, Willem Alexander Children's Hospital/Leiden University Medical Center , Leiden, the Netherlands.
authors.forename: Willemijn T
authors.initials: WT
authors.lastname: Quispel
authors.affiliation: Immunology Laboratory, Willem Alexander Children's Hospital/Leiden University Medical Center , Leiden, the Netherlands.
authors.forename: Janine A
authors.initials: JA
authors.lastname: Stegehuis-Kamp
authors.affiliation: Immunology Laboratory, Willem Alexander Children's Hospital/Leiden University Medical Center , Leiden, the Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Blijleven
authors.affiliation: Immunology Laboratory, Willem Alexander Children's Hospital/Leiden University Medical Center , Leiden, the Netherlands.
authors.forename: Susy J
authors.initials: SJ
authors.lastname: Santos
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Magda
authors.initials: M
authors.lastname: Lourda
authors.affiliation: Department of Pediatric Oncology; Emma Children's Hospital/Academic Medical Center , Amsterdam, the Netherlands.
authors.forename: Cor
authors.initials: C
authors.lastname: van den Bos
authors.affiliation: Immunology Laboratory, Willem Alexander Children's Hospital/Leiden University Medical Center , Leiden, the Netherlands.
authors.forename: Astrid G S
authors.initials: AG
authors.lastname: van Halteren
authors.affiliation: Immunology Laboratory, Willem Alexander Children's Hospital/Leiden University Medical Center, Leiden, the Netherlands; Division of Hematology/Oncology, Hospital for Sick Children/University of Toronto, Toronto, Canada.
authors.forename: R Maarten
authors.initials: RM
authors.lastname: Egeler
keywords: CXCL12; Chemokine receptor CXCR4; Langerhans cell histiocytosis; chemotaxis; prognostic marker 