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LINKS
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MASTOCITOSI:
PATOGENESI
In
diversi tipi di mastocitosi è dimostrabile la presenza di
mutazioni nel gene c-Kit (CD117). Approfondimenti
in web:
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- Proc Natl Acad Sci U S A 1999 Feb 16;96(4):1609-14
- Activating and dominant inactivating c-KIT
catalytic domain mutations in distinct clinical forms of human
mastocytosis.
Longley BJ Jr, Metcalfe DD, Tharp M, Wang X, Tyrrell L, Lu SZ,
Heitjan D, Ma Y.
Departments of Dermatology and Pathology, Section of Dermatopathology,
College of Physicians and Surgeons of Columbia University, New York,
NY 10032, USA. jack.longley@columbia.edu
Human mastocytosis is characterized by increased mast cells. It
usually occurs as a sporadic disease that is often transient and
limited in children and persistent or progressive in adults. The c-KIT
protooncogene encodes KIT, a tyrosine kinase that is the receptor for
mast cell growth factor. Because mutated KIT can transform cells, we
examined c-KIT in skin lesions of 22 patients with sporadic
mastocytosis and 3 patients with familial mastocytosis. All patients
with adult sporadic mastocytosis had somatic c-KIT mutations in codon
816 causing substitution of valine for aspartate and spontaneous
activation of mast cell growth factor receptor (P = 0.0001). A subset
of four pediatric onset cases with clinically unusual disease also had
codon 816 activating mutations substituting valine, tyrosine, or
phenylalanine for aspartate. Typical pediatric patients lacked 816
mutations, but limited sequencing showed three of six had a novel
dominant inactivating mutation substituting lysine for glutamic acid
in position 839, the site of a potential salt bridge that is highly
conserved in receptor tyrosine kinases. No c-KIT mutations were found
in the entire coding region of three patients with familial
mastocytosis. We conclude that c-KIT somatic mutations substituting
valine in position 816 of KIT are characteristic of sporadic adult
mastocytosis and may cause this disease. Similar mutations causing
activation of the mast cell growth factor receptor are found in
children apparently at risk for extensive or persistent disease. In
contrast, typical pediatric mastocytosis patients lack these mutations
and may express inactivating c-KIT mutations. Familial mastocytosis,
however, may occur in the absence of c-KIT coding mutations.
Nat Genet 1996 Mar;12(3):312-4- Somatic c-KIT activating mutation in urticaria
pigmentosa and aggressive mastocytosis: establishment of clonality in a
human mast cell neoplasm.
Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG, Duffy T, Jacobs
P, Tang LH, Modlin I.
Department of Dermatology, Yale University School of Medicine, New Haven
Connecticut 06510, USA.
Mastocytosis is characterized by accumulations of mast cells in various
organs (1). Most cases are indolent and confined to the skin, where discrete
mast cell infiltrates are associated increased epidermal melanin, a clinical
picture known as urticaria pigmentosa (UP). Other forms of mastocytosis
combine UP with aggressive involvement of other organs or with haemotologic
abnormalities (1-4). It is not known whether all forms of mastocytosis are
true neoplasms or whether some might represent reactive hyperplasias (5-7).
The c-KIT proto-oncogene encodes a type III receptor tyrosine kinase (KIT)
that is critical to the development and survival of mast cells and
melanocytes (8-11). The ligand for KIT (KL) can stimulate mast cell
development, proliferation, and mediator release (9,12-17), as well as
melanocyte proliferation and pigment production (18-20). To determine the
role of c-KIT in the pathogenesis of mastocytosis, we examined tissue and
cells isolated from a patient with UP and aggressive systemic mastocytosis
with massive splenic involvement. We found a mutation that results in
constitutive activation and expression of c-KIT in mast cells of both skin
and spleen. This is the first in situ demonstration of an activation c-KIT
mutation in neoplastic cells. It also demonstrates the clonal and neoplastic
nature of this form of mastocytes.
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