Program DHC-Virtual
20 - 21 January 2021
Abstracts Immunology session 3
Abstract
Myeloid progenitors as cells of origin in Langerhans cell histiocytosis
21 January
09:06 09:18
Y. Xiao
Paper

Bone marrow-derived myeloid progenitors as driver mutation carriers in high- and low-risk Langerhans cell histiocytosis

Yanling Xiao (1,2), Astrid G.S. van Halteren (3,4), Xin Lei (1,2), Jelske Borst (3), Eline Steenwijk (3), Tom de Wit (1,2), Joanna Grabowska (2), Rhianne Voogd (2), Paul Kemps (3), Jennifer Picarsic (5,6), Jannie Borst (1,2,5,7)
(1) Leiden University Medical Center, Department of Immunology and Oncode Institute, Leiden, (2) The Netherlands Cancer Institute, Department of Tumor Biology and Immunology, Amsterdam, (3) Leiden University Medical Center, Willem Alexander Children’s Hospital, Leiden, (4) Princess Máxima Center for Pediatric Oncology, Research Institute, Utrecht, (5) University of Pittsburgh School of Medicine, Department of Pathology, Pittsburgh, (6) Cincinnati Children’s Hospital, Division of Pathology, Cincinnati, (7) Amsterdam University Medical Center, Emma Children’s Hospital, Amsterdam
No potential conflicts of interest
Introduction

Langerhans cell histiocytosis (LCH) is a myeloid neoplasia, driven by sporadic activating mutations in the MAPK pathway. The “misguided myeloid dendritic cell (DC)” model proposes that high-risk, multisystem, risk-organ positive (MS-RO+) LCH results from driver mutation in a bone marrow (BM)-resident multipotent hematopoietic progenitor, while low-risk, MS-RO- and single system (SS) LCH would result from driver mutation in a circulating or tissue-resident, dendritic cell (DC)-committed precursor.

Methods

The CD34+c-Kit+Flt3+ population contains oligopotent progenitors of monocytes (Mo)/macrophages (MF), osteoclasts (OC) and DCs. We have examined this population as potential mutation carrier by droplet digital PCR in all LCH disease manifestations. 

Results

CD34+c-Kit+Flt3+ cells from BM of MS-RO+ LCH patients produced Langerhans cell (LC)-like cells in vitro. Both LC-like and DC offspring from this progenitor carried the BRAF mutation, confirming their common origin. In both high- and low-risk LCH patients, CD34+c-Kit+Flt3+ progenitor frequency in blood was higher than in healthy donors. In one MS-ROLCH patient, CD34+c-Kit+Flt3+ cell frequency in blood and its BRAF-mutated offspring reported response to chemotherapy. CD34+c-Kit+Flt3+ progenitors from blood of both high- and low-risk LCH patients gave rise to DC and LC-like cells in vitro, but the driver mutation was not easily detectable, likely due to low frequency of mutated progenitors. Mutant BRAF alleles were found in Mo/MF, DC, LC-like and/or OC-like cells in lesions and/or Mo and DC in blood of multiple low-risk patients. 

Conclusion

Our results therefore suggest that both in high- and low-risk LCH, the driver mutation is present in a BM-resident myeloid progenitor that can be mobilized to the blood. 

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