Mastocytosis: from a Molecular Point of View

Abstract

Mast cells (MCs) are physiologically activated by binding of stem cell factor (SCF) to the extracellular domains of the Kit receptor. This binding increases the proliferation and prolongs the survival of normal mature MCs, as well as intensifies the release of mediators. In mastocytosis, somatic mutations of the coding Kit gene cause autocrine dysregulation and lead to constitutive KIT activation even in the absence of its ligand SCF. Clinical symptoms are caused by MC-mediator release and/or infiltration of MCs into tissues. Aberrant KIT activation may result in increased production of MCs in the skin and extracutaneous organs. Depending on the affected organ(s), the disease can be divided into cutaneous mastocytosis (CM), systemic mastocytosis (SM), and localized MC tumors. The updated classification of WHO discriminates between several distinct subvariants of CM and SM. While the prognosis in CM and indolent SM (ISM) is excellent with (almost) normal life expectancy, the prognosis in aggressive SM (ASM) and MC leukemia (MCL) is dismal. The symptoms may comprise urticaria, angioedema, flush, pruritus, abdominal pain, diarrhea, hypotension, syncope, and musculoskeletal pain and are the results of MC infiltration and mediator release into target organs, i.e., the skin, gastrointestinal tract, liver, spleen, lymph nodes, and bone marrow. Mastocytosis differs from a lot of other hematological disorders because its pathology is not only based on the lack of normal function of a specific pathway or of a specific cell type but additionally is a proliferative disease. Currently available treatments of mastocytosis include symptomatic, antimediator and cytoreductive targeted therapies.

Keywords: Cutaneous mastocytosis; D816V mutation; KIT; Mast cell; SCF; Systemic mastocytosis.

Fig. 1

MCs develop from CD34+/CD117+ progenitors of bone marrow origin. Mast cell progenitors (MCP) are released from bone marrow into circulation. There they follow a controlled trafficking pattern with the help of interaction between integrins and their receptors. Finally, they reach the target tissues where under influence of growth factors they mature into mast cells

Fig. 2

MCs express a variety of chemokine and cytokine receptors on their surface. They release mediators including cytokines, de novo synthesized and stored mediators. MCs rapidly respond to environmental stimuli such as IgE-bound allergen and interact with other immune/non-immune cells

Fig. 3

Main signaling pathways in mast cell biology include Kit and FcεRI signaling. While the first pathway (in green) is associated with the cell survival and proliferation, the second pathway (in blue) has a key role in the production of the delayed de novo mediators and degranulation of the immediately released preformed mediators. SCF binding to the first three Ig-like domains of extracellular region of KIT induces structural changes resulting in dimerization of two KIT receptors following phosphorylation of intracellular regions and activation of signaling pathways. Crosslinking of IgE-bound allergen triggers the FcεRI signaling pathway (blue) initiates and results in mast cell degranulation

Fig. 4

Transgenic mice expressing the human D816VKit transgene in MCs were assessed at different ages for developing SM symptoms and compared with normal non-transgenic mice. They were found to have organ involvement in the spleen, heart, lymph nodes, and stomach but not in the bone marrow. Comparing BMMCs of these two groups of mice revealed that BMMCs from the transgenic ones became independent to SCF for proliferation and activation

Fig. 5

Features associated with release of MC mediators during mastocytosis at two levels of organ involvement (a) and cell-cytokine interactions of MCs and tissue cells (b)

Fig. 6

Comparison between CM and SM due to clinical manifestations