Langerhans cell histiocytosis: current advances in molecular pathogenesis

Abstract

Langerhans cell histiocytosis (LCH) is a rare and clinically heterogeneous hematological disease characterized by the accumulation of mononuclear phagocytes in various tissues and organs. LCH is often characterized by activating mutations of the mitogen-activated protein kinase (MAPK) pathway with BRAF^V600E being the most recurrent mutation. Although this discovery has greatly helped in understanding the disease and in developing better investigational tools, the process of malignant transformation and the cell of origin are still not fully understood. In this review, we focus on the newest updates regarding the molecular pathogenesis of LCH and novel suggested pathways with treatment potential.

Keywords: BRAFV600E; MAP2K1; dendritic cells; langerhans cell histiocytosis; monocytes; oncogene; senescence.

Figure 1

LCH classification. Main types of classification of LCH cases based on the number of lesions and number and type of organs involved. Created with Biorender.com.

Figure 2

RAS/RAF/MEK/ERK signaling pathway. Under homeostatic conditions the RAS/RAF/MEK/ERK is activated through the binding of extracellular ligands (i.e. hormones, growth factors, and cytokines) to receptor tyrosine kinases (RTKs) leading to dimerization and phosphorylation. In turn, this leads to the induction of the active form RAS-GTP, which leads to a downstream cascade that is characterized by the activation through phosphorylation of Raf, MEK, and ERK. Activated ERK can then trigger the transcription of numerous genes involved in the growth, proliferation, and survival of the cell. In the presence of activating mutations of Raf (i.e. BRAF^V600E ) or MEK (MAP2K1 mutations), this pathway becomes constitutively active independent of the ligand-receptor interaction. Constitutive activation of the pathway can consequently lead to oncogenesis through induced cell differentiation, resistance to apoptosis, and oncogene-induced senescence. Created with Biorender.com.

Figure 3

Past and present models of LCH. (A) The “Activated-Immature” model of LCH was one of the first models proposed. In this model, it was proposed that LCH was a consequence of the malignant transformation of LCs present in the dermis. Through this malignant transformation, the aberrant LCs could proliferate, migrate, and form lesions in numerous compartments of the human body. The “Activated-Immature” model of LCH was then replaced by (B) the “Misguided Myeloid DC precursor” model. This model suggests that LCH cells can arise from different myeloid precursors and the stage of differentiation of the precursor cells will determine the severity of the disease. Created with Biorender.com.

Figure 4

LCH lesion composition. The composition of LCH lesions is very heterogenous with the presence of different components of the immune system. Crosstalk between the LCH cells and the infiltrating immune cells contributes to the formation of a highly inflammatory and dysfunctional microenvironment that inhibits the clearance of the LCH cells by the immune cells and favors their persistence and survival in the lesions. Created with Biorender.com.