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Review
. 2022 Dec 19;20(1):195.
doi: 10.1186/s12964-022-00917-0.

Signaling pathways, microenvironment, and targeted treatments in Langerhans cell histiocytosis

Xue-Min Gao  1   2 , Jian Li  1   2 , Xin-Xin Cao  3   4
Affiliations
Review

Signaling pathways, microenvironment, and targeted treatments in Langerhans cell histiocytosis

Xue-Min Gao et al. Cell Commun Signal. .

Abstract

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid malignancy in the "L-group" histiocytosis. Mitogen-activated protein kinase (MAPK) pathway activating mutations are detectable in nearly all LCH lesions. However, the pathogenic roles of MAPK pathway activation in the development of histiocytosis are still elusive. This review will summarize research concerning the landscape and pathogenic roles of MAPK pathway mutations and related treatment opportunities in Langerhans cell histiocytosis. Video abstract.

Keywords: Inflammatory myeloid malignancy; Langerhans cell histiocytosis (LCH); MAPK pathway; MEK inhibitors; Progenitor cells; RAF inhibitors.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Schematic depicting the domain of BRAF and MAP2K1, and major mutations identified in LCH. A BRAF comprises three main domains, the RAS-binding domain (120–280 amino acids), hinge domain, and kinase domain (457–717 amino acids). V600 mutation belongs to class I BRAF mutation, resulting in an activated monomer of the Braf molecule. The N486_P490del mutation results in a shortened β3-αC3 loop of the Braf molecule. B MAP2K1 comprises three main domains, the ERK-binding domain (EBD), negative-regulatory domain (NRR), and kinase domain (68–361 amino acids). MAP2K1 mutations found in LCH were mainly class II (RAF-regulated) and class III (RAF-independent) mutations
Fig. 2
Fig. 2
Schematic depicting of BRAF-monomer with different mutation and their sensitivity to BRAF inhibitors. A Class I mutations result in an active form BRAF monomer, the αC3 is in the OUT position, making it sensitive to αC-out BRAF inhibitors. B The β3-αC3 loop deletion shortens the loop, forced the αC3 in the IN positive, and makes it insensitive to αC-out BRAF inhibitors, but sensitive to αC-in BRAF inhibitors
Fig. 3
Fig. 3
Signaling pathways, microenvironment, and targeted treatments in Langerhans cell histiocytosis. A The precursor cells of LCH cells. (a) Early myeloid progenitor cells are the precursor cells of LCH cells, regardless of the risk of disease. MAPK pathway activation promotes the proliferation and differentiation of precursor cells. (b) The direct precursor cells of LCH cells in peripheral blood are still controversial. B MAPK pathway mutations and treatments targeting specific mutations. C LCH cells seeded the tumor microenvironment. (a) The interaction between LCH cells and Tregs via ICOS-ICOS ligand promotes the accumulation of Tregs in the microenvironment, which promotes an immunosuppressive microenvironment. (b) The interaction between LCH cells and CD8+ T cells via PD-1 and PD-L1 suppresses CD8+ T cell function and helps LCH cells escape immunosurveillance. PD-1 inhibitors act in synergy with MAPK inhibitors. (c) CCL5 produced by LCH cells promotes the accumulation of eosinophils in lesions via chemotaxis. D Survival and accumulation of LCH cells induce the formation of lesions. (a) The activation of the MAPK pathway in LCH cells upregulates BCL-XL expression in LCH cells and promotes the survival of those cells. (b) The activation of the MAPK pathway in LCH cells downregulates CCR7 expression on the cell membrane via negative feedback, inhibits the migration of LCH cells to draining lymph nodes, and promotes LCH cell accumulation in lesions
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