Biology and pathophysiology of human mastocytosis

Mastocytosis is a term collectively used for a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells. Clinical symptoms occur from the release of chemical mediators and the pathologic infiltration of cells. Three major groups of patients with mastocytosis have to be distinguish: i) cutaneous mastocytosis, ii) mastocytosis involving the skin and one or more extracutaneous organ(s), and iii) visceral mastocytosis without involvement of the skin. Groups ii) and iii) account for approximately 15-20% of all cases and have been refered to as systemic mastocytosis. Cutaneous mastocytosis typically develops in childhood and presents as urticaria pigmentose or diffuse cutaneous mastocytosis. Patients suffering from cutaneous mastocytosis usually have a benign clinical course. By contrast, systemic mastocytosis is a diffuse hematologic process with an increased risk to develop aggressive disease. In these patients, additional hematological abnormalities or a second hematologic disease process, such as a myeloprliferative or myelodysplastic syndrome may develop. Malignant mastocytosis and mast cell leukemia are aggressive forms of mastocytosis, characterized by uncontrolled and progressive proliferation and infiltration of mast cells in diverse organs. These patients usually present without cutaneous lesions and have an unfavorable prognosis. Because of immature cell morphology, lack of cutaneous lesions and complex histophathology, it is often difficult to establish the diagnosis mastocytosis in such patients. Little is known so far about the biology and pathophsiology of human mastocytosis. Recent observations suggest, that most variants of mastocytosis represent clonal (neoplastic) disease-processes involving a more or less immature mast cell progenito cell. Other observations have suggested that mastocytosis is associated with deregulation(s) of genes coding for MGF (mast cell growth factor) or MGF-receptor, which is encoded by the c-kit (W) proto-oncogen. More recently, point mutations in the kinase-domain of c-kit have been detected in patients with mastocytosis, and have been linked to MGF-independent cell-growth. However only a subpolulation of patients with aggressive mastocytosis exhibit c-kit point mutations, and other molecular defects that may account for abnormal (autonomous) mast cell growth or that would control cell-proliferation, have not been identified yet. Also, no effective therapy for patients with malignant mastocytosis or mast cell leukemia is known. The aims of the present project are to characterize in detail the biologic, phenotypic and functional properties of abnormal (neoplastic) cells in human mastocytosis in order to i) improve our knowledge concerning disease, ii) improve the diagnostic potential, iii) achieve a better classification of disease, iv) identify (new) drugs with a potential effect in mastocytosis, and v) establish new therapeutic concepts for the (various) malignant variants of disease.