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C H A P T E R 72

MAST CELLS AND MASTOCYTOSIS

Jason Gotlib, Hans-Peter Horny, and Peter Valent

INTRODUCTION of proliferation, and subsequently undergo apoptosis after their
recruitment and activation in the tissues. Differential expression of
The year 2015 marked a century since the death of Paul Ehrlich, who the transcription factor CCAAT-enhancer-binding protein (CEBP)α
used his 1878 doctoral thesis to characterize a new cell type—the may be a primary determinant of whether development is skewed
mast cell (MC)—based on its reactivity to aniline dyes and the toward basophil progenitors (CEBPα present) or MC progenitors
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metachromatic appearance of its cytoplasmic granules. He referred (CEBPα absent). Although eosinophils and basophils have been
to MCs as Mastzellen and he speculated that their intracellular found to share a common bipotential progenitor in humans, defini-
granules contained phagocytosed materials or nutrients. Ehrlich also tive data for a similar progenitor giving rise to both basophils and
described a close relationship in tissues between MCs and blood MCs are lacking. Rather, based on colony assays, MCs are directly
vessels, nerves, gland excretory ducts, as well as their proximity within derived from multilineage and lineage-restricted progenitors, but not
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the environment of tumors and chronic inflammation. In 1894, the from such a bi-potent precursor cell. In line with this observation,
pathobiologic association of MCs with lesions of urticaria pigmentosa evidence against a bilineage basophil/MC progenitor also came from
was reported, and from the 1930s forward, basic incremental discov- tracking lineage involvement of KIT D816V in patients with SM,
eries about normal MC functions were made. Their capacity to where KIT D816V was only found in basophils in a small subset
undergo degranulation in response to various stimuli, their source of of patients, namely those with multilineage involvement of the
histamine and heparin, and their important role in anaphylaxis was mutation. In addition, when highly enriched by cell sorting, neither
examined. 2 mature blood basophils nor mature blood monocytes give rise to
Perturbations of MC growth and function may lead to mastocy- MCs in vitro. 6
tosis, a condition defined by pathologic expansion and accumulation
of MCs in diverse tissues such as the skin, bone marrow (BM), spleen,
liver, lymph nodes, and gastrointestinal tract. In 1949 the first case KIT and Stem Cell Factor (KIT Ligand)
report of systemic mastocytosis (SM) was published. Later, between
1950 and 1980, several different subtypes of SM were described, KIT
including a leukemic variant termed mast cell leukemia (MCL). The
first classification of mastocytosis was created by the Kiel group of Kit is the cellular homolog of the v-Kit oncogene of the Hardy-
pathologists, and in 1991 the first consensus classification was pub- Zuckerman 4 feline sarcoma virus. The human KIT gene on chromo-
lished. Criteria for SM and other variants of the disease were estab- some 4q11–12 was found to be allelic to the white spotting locus (W)
lished between 1990 and 2000. In 2000 these criteria were discussed in mice, in which over 30 mutations have been identified. The common
by a consensus group and were employed to establish a robust con- theme of mutant alleles at the W locus is decreased kit kinase activity
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sensus classification of mastocytosis, that was adopted by the World either through missense mutations that generate kinase-defective kit
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v
Health Organization (WHO) in 2001 and also in 2008. In consecu- (e.g., W [kit D790N]; W [kit E582K]; W [kit T660M]; and W
tive years, the consensus group published treatment response criteria [kit V831M]) or decreased expression of kit on the cell surface (e.g.,
and established a widely accepted update of the classification of the W allele, caused by a 78-amino acid deletion that involves the
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mastocytosis in 2007. In this updated classification, the smoldering transmembrane region of the kit protein).
state is defined as a separate category of SM which was confirmed by Double mutants at the murine W locus not only result in mark-
the WHO in 2016. In 2002 the European Competence Network on edly decreased MC numbers, but also in pleiotropic phenotypes,
Mastocytosis (ECNM) was founded. Since then, the ECNM has including white coat color/spotting, sterility, and anemia, that respec-
facilitated basic science and translational research dealing with mas- tively relate to the failure of melanocytes, germ cells, and hematopoi-
tocytosis and related MC disorders. This chapter provides an overview etic progenitors to migrate and/or proliferate effectively during
of normal MC physiology and highlights contemporary issues related development. Heterozygosity or homozygosity for the different alleles
to the classification, diagnosis, and treatment of SM. at the W locus results in variable phenotypic effects on hematopoiesis,
pigmentation, and fertility. Mutations at the W locus can also result
in abnormalities of the interstitial pacemaker cells of Cajal, leading
ORIGIN AND DEVELOPMENT OF MAST CELLS to functional gut abnormalities, such as megacolon. Intriguingly,
some of these clinical correlates can also be seen in patients undergo-
The marrow origin of MCs was first demonstrated by engrafting ing long-term treatment with a strong KIT inhibitor, like imatinib:
BM cells into irradiated mice. Human MCs can be generated from these individuals can develop MC deficiency, depigmented skin areas,
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a CD34 hematopoietic progenitor cell in response to stimulation cytopenias, and fertility problems.
with stem cell factor (SCF). In vitro MC differentiation models KIT is a member of the type III receptor tyrosine kinases (TKs)
showed that circulating MC progenitors express CD13, CD34, and that also include platelet-derived growth factor receptor (PDGFR)-α
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KIT, but lack CD14 and CD17. MC progenitors are released from and -β, FMS-like tyrosine kinase-3 (FLT3), vascular endothelial
the BM into the circulation in a primitive state and undergo termi- growth factor receptor 2 (VEGFR2), and the receptor for macrophage
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nal maturation and differentiation after their migration to tissues. colony-stimulating factor (FMS). These TKs share common struc-
Although shared histomorphologic and biologic features of MCs tural motifs including an extracellular domain containing five Ig-like
and basophils include cytoplasmic basophilic granules, expression of motifs that bind their specific ligands, a short transmembrane (TM)
high-affinity immunoglobulin (Ig)E receptors (FcεRI), and release domain that anchors KIT to the cell membrane, a cytoplasmic TK
of histamine upon stimulation, basophils exhibit several distinctive domain that is split by an insert sequence into ATP-binding and
characteristics. Basophils circulate as mature cells, which are incapable phosphotransferase regions, and a juxtamembrane (JM) domain that
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