Mastocytosis: from a Molecular Point of View
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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.
KeywordsCutaneous mastocytosis D816V mutation KIT Mast cell SCF Systemic mastocytosis
Mucosal addressin cell adhesion molecule-1
Vascular cell adhesion molecule-1
Nerve growth factor
Stem cell factor
Indolent systemic mastocytosis
Baseline serum tryptase
Allogeneic hematopoietic stem cell transplantation
Mast cells (MCs) are normal residents of mucosal tissues, but their numbers and anatomical location change markedly during immune responses, infections, and other disorders . In most settings, MCs have become infamous for their detrimental actions, i.e., anaphylaxis, allergy, arthritis, atherosclerosis, and cancer while in some settings, notably host defense against bacteria, parasites, and envenomation, their biologic function is in favor of maintaining health . MC progenitor cells express the tyrosine kinase receptor KIT (CD117). Normally, the interaction between this oncogenic receptor and its ligand, stem cell factor (SCF), induces MC development in uncommitted and MC-committed hematopoietic precursor cells . Mastocytosis is a heterogeneous group of disorders involving MCs and their CD34+/CD117+ progenitors. It is a group of rare clonal disorders of bone marrow origin characterized by abnormal growth and/or accumulation of clonal MCs primarily in the skin and bone marrow. Neoplastic MCs expressing CD25 and/or CD2 were described in systemic mastocytosis especially in aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) [4, 5]. The symptoms of mast cell activation include sudden onset of flush, urticaria, angioedema, pruritus, abdominal pain, headache, diarrhea, hypotension, syncope, and musculoskeletal pain which are the results of MC mediator release and infiltration into target organs . The heterogeneity of clinical presentation in mastocytosis is a result of MC burden and MC activity , the type of skin lesions, the patient’s age at the onset, and the associated hematological disorders. The typical mastocytosis of childhood is usually cutaneous and transient whereas in adulthood the systemic form is more common . MCs respond to surrounding stimuli through the expression of a variety of receptors including FcεRI and KIT (CD117). MCs require stem cell factor (SCF) binding to their surface receptor KIT for homeostasis . In mastocytosis, the presence of mutations within different regions of KIT in the extracellular, transmembrane, juxtamembrane domains, or activating loop interrupts the normal signaling cascade characterized by constitutive receptor activation independent from SCF .
Mast Cell Origin and Development
MCs are innate immune cells known for their role in allergic and anaphylactic reactions. They functionally can be considered a double-edged knife with both good and bad sides. The bad consists in type I allergic immune responses through crosslinking FcεR1 via allergen-bound IgE. On the good side the MC cell plays a protective key role in the battle against some environmental threats such as the venoms of reptiles and insects [10, 11]. In this regard, MC-derived carboxypeptidase plays a key role in degradation of the snake venom toxin safarotoxin . Owing to expression of a wide range of receptors and release of a broad spectrum of mediators, they play a key role in acquired and innate immunity . MCs arise from hematopoietic progenitor cells and mature MCs ordinarily do not circulate in the blood but migrate into peripheral tissues where they acquire their mature phenotype . CD34+/CD117+ pluripotent progenitor cells from bone marrow origin circulate in the blood as committed precursors and under influence of SCF develop into mature FcεR1+ and CD117+ MCs in peripheral tissues [15, 16, 17]. SCF, which is produced by a variety of cells including fibroblasts and endothelial cells, promotes the recruitment of MC progenitors into tissues, as well as their local maturation and activation. Its receptor, c-Kit (CD117), is a type III tyrosine kinase broadly expressed on mature MCs and eosinophils . In addition to SCF, MC growth and survival modulators include nerve growth factor (NGF) , IL-9 , CXCL12, IL-3, IL-4, IL-10, IL-33, and TGF-β [1, 14].
Mast Cell Tissue Homing
Mast Cell Mediators and Receptors
Stem Cell Factor
The knowledge about the molecular structure of the KIT receptor and the further intracellular signaling cascade upon binding to SCF is a prerequisite for a better understanding of the pathogenesis of mastocytosis and is also the basis for treatments targeting this receptor. The discovery of the dimeric molecule SCF (also known as Kit Ligand, Steel Factor, or Mast Cell Growth Factor) and KIT was based on experimental single gene-induced anemias in mice which led to the identification of the W and Steel (Sl) loci. Mutations at either of these loci were shown to cause alterations of fur color, anemia and lack of tissue MCs . Genomic investigations by Geissler et al. revealed that SCF in humans maps on chromosome 12, between 12q14.3 and 12qter . SCF exists both as a membrane-bound and a soluble form expressed by fibroblasts and endothelial cells throughout the whole body [36, 37]. It is synthesized from two alternatively spliced messenger RNAs (mRNAs) as transmembrane proteins which are enzymatically cleaved to produce soluble forms or act as cell associated molecules . Both SCF variants have distinct roles in the survival and proliferation of hematopoietic cells. Using the Sl/Sld mouse model in which mutants were generated that express only soluble SCF or membrane restricted SCF, it was reported that soluble SCF is responsible for proliferation of myeloid progenitors (in concert with other cytokines), while only the membrane bound form is able partially to correct the runting and the bone marrow hypocellularity that are seen in these mice .
SCF-KIT Interaction and Mediated Signaling
Symptoms of Mediator Release
The umbrella term mast cell activation disease (MCAD) comprises the full spectrum of primary systemic MC disease, i.e., systemic mastocytosis (SM) which is further divided into the subtypes primary MC activation syndrome (MCAS) and MC leukemia (MCL) . Aberrant release of mast cell mediators is responsible for related symptoms in mast cell activation disorders. Histamine is responsible for the immediate symptoms including headache, hypotension, pruritus, urticaria, angioedema, diarrhea, and anaphylaxis. Symptoms such as cardiac arrhythmias, myocardial infarction, and hypotension may be attributed to aberrant chymase release. Abdominal cramping, pulmonary edema, urticaria, bronchoconstriction, hypotension, arrhythmia, and anaphylaxis are associated with the release of platelet activating factor (PAF). Prostaglandin D2 is responsible for symptoms such as flushing, mucus secretion, bronchoconstriction, vascular instability, headache, nausea, and abdominal pain . Mast cell activation syndromes (MCAS) are a group of disorders that typically present with symptoms of MC mediator release including itching, flushing, whealing, flaring, angioedema, tachycardia, headache, and gastrointestinal manifestations such as abdominal pain and diarrhea . The proposed diagnostic criteria for MCAS include episodic recurrent symptoms consistent with MC activation in more than one organ; decrease in frequency/severity of symptoms in response to MC mediator therapy such as H1 and H2 antihistamines, leukotrienes, cromolyn, and glucocorticoids; and increased MC activation products mainly tryptase above baseline in at least two symptomatic episodes . Other MC products that can be found above normal during MCAS include heparin and chromogranin A in the blood or histamine and its metabolites (e.g., N-methylhistamine) in the urine . Lack of distinguishing cardinal signs and symptoms makes it hard to clearly distinguish mastocytosis and MCAS. Widespread distribution of MCs and various pattern of aberrant mediator expression result in a great diversity in the clinical presentation of MCAS. Generally, MCAS does not include the entire body, but may involve a specific organ, such as the bladder or GI tract . Unlike SM, urticaria and angioedema are often present in MCAS. MC shape in bone marrow differs in both diseases in which spindled MCs could be seen in mastocytosis while MCs are round and fully granulated in bone marrow specimens obtained from patients with MCAS . In patients with MCAS, hymenoptera stings, alcohol, and heat are the most common triggers of symptoms .
WHO systemic mastocytosis variants
Cutaneous mastocytosis (CM)
Organ involved: skin 
Molecular abnormality: KIT D816F, KIT E839K, KIT D816Y 
Urticaria pigmentosa (UP)
Characterized by fixed, reddish brown lesions which occur as maculo-papules, plaques, nodules or blisters .
Maculopapular CM (MPCM)
Small monomorphic lesions
Diffuse CM (DCM)
Rare, severe, variant which occurs mainly in infants. Blistering generalized erythroderma, nodules, and plaques are observed .
Indolent systemic mastocytosis (ISM)
No evidence of organ dysfunction .
Therapy: antimediator therapy 
Prevalence ~10% 
Isolated bone marrow mastocytosis
Systemic mastocytosis with an associated clonal hematologic non-mast cell
Lineage disease (SM-AHNMD)
Prevalence ~1% 
Aggressive systemic mastocytosis (ASM)
Impairment of organ function, organomegaly (particularly splenomegaly), cachexia or osteolyses .
Therapy: chemotherapy and stem cell transplantation 
Prevalence ~5% 
Mast cell leukemia (MCL)
Very aggressive .
Prevalence <1% 
Therapy: chemotherapy and stem cell transplantation 
Mast cell sarcoma
Aggressive neoplasm composed of cytologically malignant MCs presenting as a solitary mass .
Prevalence <1% 
Unifocal MC tumor with low-grade cellular atypia and non-destructive features 
Prevalence <1% 
Diagnostic criteria for systemic mastocytosis
Multifocal infiltrates of MC in bone marrow sections or other extracutaneous organ(s) (>15 MCs in aggregate)
• More than 25% of BMMC or MCs of extracutaneous organ(s) are spindle-shaped.
• KIT mutation at codon 816 in extracutaneous organ(s)
• Presence of CD2+ and/or CD25+ BMMCs
• Basal serum tryptase >20 ng/ml (not for patients with AHNMD-type disease)
The diagnosis of mastocytosis can be based on the histological examination of a skin biopsy for CM (if necessary and in patients who are suspected clinically in accordance with the recommendation of WHO), and the BM biopsy for the systemic forms according to the recommendation of WHO . The co-expression of KIT and tryptase in MCs in BM makes them easy to detect in histological sections by immunostaining . MCs in SM are characterized by the expression of CD25 and CD2 and an abnormal spindle-shaped hypogranular morphology tending to form clusters around blood vessels and paratrabecular and interstitial areas in the BM . Indolent systemic mastocytosis (ISM) is the least severe systemic variant which is not a life threatening disease . ISM without skin lesions has been frequently reported in those with systemic allergic reactions to hymenoptera venom and raised basal serum tryptase . Gastrointestinal symptoms including abdominal pain, diarrhea, nausea, vomiting, and bloating are found in SM . Up to 28% of patients with SM have peripheral eosinophilia (>650 cells/mm3), and this frequency increases in advanced forms . Neoplastic MCs in ASM and MCL, but not ISM, preferentially express CD30 which correlates with a poor overall prognosis . Additionally, myeloproliferative or myelodysplastic syndromes can be observed in patients with SM . Several different staging investigations need to be performed from the BM in patients with SM including microscopic investigations on smears stained with Wright-Giemsa, histology and immunohistochemistry (IHC), cytogenetics, flow cytometry for documenting the expression of CD2 and/or CD25 on neoplastic MCs, and PCR to detect KIT D816V [3, 82]. Generally, the life expectancy in patients with SM depends on the diagnosed variant in which indolent forms do not shorten life expectancy whereas advanced SM variants, including MCL, SM-AHNMD, and ASM have survival rates ranging from months to a few years despite cytoreductive therapy .
Approximately 40% suffer from SM. SM may be associated with other hematologic neoplasms not confined to the MC lineage . For example, Tschandl et al. described in a case report a 61-year-old patient with three diseases occurring synchronously: CMML, xanthogranulomas, and systemic mastocytosis . Coincidence of SM with other diseases such as pulmonary interstitial disease , refractory pruritus and cirrhosis , and Kounis syndrome  has been documented in case reports. New potential biomarkers for predicting episodes of mediator release and monitoring the treatment were described recently. For example, Ehara et al. found the Melanoma inhibitory activity (MIA), an 11-kD protein used as a serum marker for malignant melanoma, to be elevated in children with CM . Not only serum biomarkers but also MC surface markers may be of importance in the diagnosis and classification of the disease. Although co-expression of CD2 and CD25 has been known as a typical feature of neoplastic MCs for several decades, recently also other markers such as CD63, CD69, CD58, CD33, and several complement-associated molecules such as CD11c and CD35 have been found to be overexpressed in these cells. Immunophenotyping of MCs using these markers through flow cytometry revealed that MCs in ASM are of the CD25+CD2−CD63+CD69+ whereas MCs in MCL of the CD25+CD2−CD63−CD69− phenotype .
Control of the immediate, possibly severe symptoms is a common component in disease management of mastocytosis regardless of the subtype. For instance, H1-antihistamines are commonly used for the reduction of pruritus and flushing, H2-antihistamines to treat gastrointestinal (GI) symptoms, and corticosteroids and/or analgesics for mitigating bone pain and other symptoms . Cromoglicinic acid is only weakly effective but may act as adjuvant MC stabilizer through reducing the calcium influx for MC degranulation following FcεR1 crosslinking especially for GI symptoms. Furthermore, ketotifen acts in the same way as other H1-antihistamines because of its stabilizing effects. Omalizumab (Xolair®, Novartis), a humanized murine monoclonal antibody with ability to conjugate in vivo with free serum IgE, is able to reduce binding to FCεRI on MCs and basophils and can be used as an additional measure for controlling the immediate symptoms of MC activation . Oral glucocorticoids, through decreasing the number of connective tissue MCs in a dose-dependent fashion, inhibit SCF production and decrease FcεR1 expression and chemokine receptors including CCR3. Acetylic salicylic acid (Aspirin®, Bayer), a non-steroidal antiinflammatory drug (NSAID), has positive effects in patients with mastocytosis by normalizing the levels of PGD2 metabolites through irreversible inhibition of the cyclooxygenase (COX) isoenzymes. Interferon-α (IFN-α) and cladribine (2-CdA) are used in patients with aggressive SM. IFN-α acts through several mechanisms including decreasing MC mediator release, organ infiltration and normalization of serum tryptase level . Imatinib mesylate (Gleevec®, Novartis) is an ATP-competitive, orally bioavailable agent and the only FDA-approved inhibitor of various tyrosine kinases including ABL1, platelet-derived growth factor receptor (PDGFR), ARG, and KIT for use in patients with ASM without D816V KIT or wild type KIT or sporadic KIT mutant isoforms in SM, such as KIT F522C [66, 92]. Moreover, it has therapeutic applications in chronic myelogenous leukemia and gastrointestinal stromal tumors [93, 94]. Other tyrosine kinase inhibitors include Nilotinib (targets Breakpoint Cluster Region-Abelson (BCR-ABL), KIT, and PDGFR), Dasatinib (targets BCR-ABL, SRC, and KIT), Masitinib (multitargeted inhibitor of the KIT, PDGFR, fibroblast growth factor receptor 3, and Lyn tyrosine kinases), and Midostaurin also known as PKC412 (inhibitor of KIT, fms-related tyrosine kinase 3, vascular endothelial growth factor receptor 2, and PDGFR) . Clinical trials are investigating treatment particularly with KIT D816V inhibitors to be approved officially by FDA . Furthermore, narrowband ultraviolet (UVB) phototherapy is an alternative treatment option in patients with CM . Ustun et al. investigated the effectiveness of allogeneic hematopoietic stem-cell transplantation (alloHCT) in patients with advanced SM, who had undergone either sibling or unrelated alloHCT. Three parameters were used to assess response before and after transplantation including the percentage of bone marrow MCs, serum tryptase levels, and organ involvement. The median bone marrow MC percentage in biopsies and the levels of serum tryptase showed a significant decrease after transplantation. They reported that alloHCT can confer long-term overall survival . Baumgartner et al. showed that neoplastic MCs in patients with SM exhibit phosphorylated STAT5 (pSTAT5) in cytoplasm as an essential growth/survival factor, so targeting of pSTAT5 apparently could be an approach in treatment of SM . Moreover, Sharma et al. investigated the role of SHP2/PTPN11 phosphatase in oncogenic KIT signaling using an aggressive SM mouse model. They reported that stable knockdown of SHP2 results in impaired growth, colony formation, and increased rates of apoptosis in mouse mastocytoma cell line P815 harboring KITD814Y mutation .
Mastocytosis is a group of rare clonal disorders characterized by abnormal expansion and accumulation of tissue MCs in one or multiple organs. Trafficking patterns of neoplastic MCs within the BM and also augmented angiogenesis in the BM during SM in particular are interesting aspects of this disease and should be addressed in further investigations. The clonal nature of the disease can be established through the demonstration of gain-of-function mutations involving the tyrosine kinase domain of KIT receptor in skin and/or BM cells. The heterogeneity of clinical presentations of mastocytosis relates to the tissue MC burden. There is much variation in the type of skin lesions, the patient’s age at the onset, and associated hematological disorders that—taken together—make the treatment of the disease challenging. The clinical symptoms are mediated by the release of MC mediators. Management of patients within all categories of mastocytosis includes avoidance of triggering factors such as allergen. Additionally, continuous training for the correct application of the rescue self-medication (including self-injectable intramuscular epinephrine and, as warranted, antihistamine and corticosteroids) for patients and children that are at increased risk of anaphylaxis is constantly required. In recent years, various tyrosine kinase inhibitors have also been employed in order to reduce the MC-load for SM. However, currently, there is no approved tyrosine kinase inhibitor to inhibit the D816V c-kit mutation for routine settings. Moreover, most drugs including KIT D816V blocking agents have not demonstrated a promising efficacy in achieving a long-lasting remission in patients with advanced SM.
Open access funding provided by Medical University of Vienna.
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I hereby state that none of the coauthors and the corresponding author of this paper have a conflict of interest and it has been prepared for publication without using any funding. Moreover, the paper does not contain any studies with human participants or animals performed by any of the authors.
Conflict of Interest
The authors declare that they have no conflict of interest.
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