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

Abstract

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. We have examined the CD34+c-Kit+Flt3+ myeloid progenitor population as potential mutation carrier in all LCH disease manifestations. This population contains oligopotent progenitors of monocytes (Mo)/macrophages (MF), osteoclasts (OC) and DCs. 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-RO+ LCH 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. We therefore hypothesize 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.

Langerhans cell histiocytosis: A malignant myeloid neoplasm or disorder of immune regulation?

“…Although a number of studies have suggested that LCH cells may be derived from early myeloid precursors (immature CD1a‐positive dendritic cells), these data are not sufficient to conclude that LCH is a malignancy. Additionally, BRAF mutations have recently been identified in many cell lineages in patients with LCH, including lymphoid populations such as B cells, T cells and natural killer cells 18 …”

“…Additionally, BRAF mutations have recently been identified in many cell lineages in patients with LCH, including lymphoid populations such as B cells, T cells and natural killer cells. 18 …”

A circulating subset of BRAFV600E‐positive cells in infants with high‐risk Langerhans cell histiocytosis treated with BRAF inhibitors

“…Recent studies have suggested that, particularly in young infants with RO + MS LCH, the clonal origin of the pathological BRAF V600E ‐mutated histiocytes may originate from haematopoietic stem cells. One argument in favour of this hypothesis is that, in addition to the pathological CD1a + CD207 + histiocytes of the lesions, other cells carry the BRAF V600E mutation, including monocytes, myeloid dendritic cells (mDCs), plasmacytoid dendritic cells (pDCs), and less frequently, B and T lymphocytes 6–8 . However, previous studies have included very low numbers of patients, and the kinetics of these subsets of BRAF V600E ‐mutated circulating blood cells during the natural course of the disease remains unknown.…”

Does CD1a Expression Influence T Cell Function in Patients With Langerhans Cell Histiocytosis?

“…LCH cells commonly harbor RAS/RAF/MEK/ERK pathway mutations, the most frequent of which is BRAF V600E (4)(5)(6)(7)(8)(9)(10). LCH cells are suggested mostly to have myeloid cell origin and similarities with antigen presenting cell lineages (11)(12)(13)(14)(15), although some lesions were recently found to arise upstream of these lineages in multipotent progenitor cells (16). Given the comparability with antigen presenting cell lineages, LCH cells likely have the ability to interact directly with T cells through contact-dependent and -independent manners.…”

“…Given the comparability with antigen presenting cell lineages, LCH cells likely have the ability to interact directly with T cells through contact-dependent and -independent manners. Additionally, BRAF V600 mutations have been detected in lymphocytes in a few instances (16,17). T cells thus may be critical to LCH pathogenesis and indeed this has already been suggested for various reasons, such as the presence of cytokines suggestive of T cell activation (18,19), and an enrichment of Foxp3+ regulatory T cells (Tregs), which are known for their immunosuppressive properties, within lesions (7-30% of total T cells) and blood from patients with active LCH (20,21).…”