Mastocytosis is a hematopoietic neoplasm defined by abnormal expansion and focal accumulation of clonal tissue mast cells in various organ-systems. The disease exhibits a complex pathology and an equally complex clinical behavior. The classification of the World Health Organization (WHO) divides mastocytosis into cutaneous forms, systemic variants, and localized mast cell tumors. In >80% of patients with systemic mastocytosis (SM), a somatic point mutation in KIT at codon 816 is found. Whereas patients with indolent forms of the disease have a normal or near-normal life expectancy, patients with advanced mast cell neoplasms, including aggressive SM and mast cell leukemia, have a poor prognosis with short survival times. In a majority of these patients, multiple somatic mutations and/or an associated hematologic neoplasm, such as a myeloid leukemia, may be detected. Independent of the category of mastocytosis and the serum tryptase level, patients may suffer from mediator-related symptoms and/or osteopathy. Depending on the presence of co-morbidities, the symptomatology in such patients may be mild, severe or even life-threatening. Most relevant co-morbidities in such patients are IgE-dependent allergies, psychiatric, psychological or mental problems, and vitamin D deficiency. The diagnosis and management of mastocytosis is an emerging challenge in clinical practice and requires vast knowledge, a multidisciplinary approach, and personalized medicine procedures. In this article, the current knowledge about mastocytosis is reviewed with special emphasis on the multidisciplinary aspects of the disease and related challenges in daily practice.

Chronic myeloid leukemia and systemic mastocytosis are myeloid neoplasms sharing a number of pathogenetic and clinical features. In both conditions, an aberrantly activated oncoprotein with tyrosine kinase activity, namely BCR-ABL1 in chronic myeloid leukemia, and mutant KIT, mostly KIT D816V, in systemic mastocytosis, is key to disease evolution. The appreciation of the role of such tyrosine kinases in these diseases has led to the development of improved therapies with tyrosine kinase-targeted inhibitors. However, most drugs, including new KIT D816V-blocking agents, have failed to achieve long-lasting remissions in advanced systemic mastocytosis, and there is a similar problem in chronic myeloid leukemia, where imatinib-resistant patients sometimes fail to achieve remission, even with second- or third-line BCR-ABL1 specific tyrosine kinase inhibitors. During disease progression, additional signaling pathways become activated in neoplastic cells, but most converge into major downstream networks. Among these, the AKT and STAT5 pathways appear most critical and may result in drug-resistant chronic myeloid leukemia and systemic mastocytosis. Inhibition of phosphorylation of these targets has proven their crucial role in disease-evolution in both malignancies. Together, these observations suggest that STAT5 and AKT are key drivers of oncogenesis in drug-resistant forms of the diseases, and that targeting STAT5 and AKT might be an interesting approach in these malignancies. The present article provides an overview of our current knowledge about the critical role of AKT and STAT5 in the pathophysiology of chronic myeloid leukemia and systemic mastocytosis and on their potential value as therapeutic targets in these neoplasms.

Mastocytosis is a term referring to a heterogeneous group of disorders characterized by abnormal mast cell (MC) accumulation in the skin and/or internal organs. In children, the disease involves mostly the skin (cutaneous mastocytosis;CM), whereas in adults, the disease is usually systemic (systemic mastocytosis;SM). AdvancedSMvariants with end‐organ damage and reduced life expectancy have also been described, but are rare. Clinical signs and symptoms inSMresult from excessive mediator release byMCs and, in aggressive forms, from organ failure related toMCinfiltration. As a consequence, treatment of indolentSMaims primarily at the control of symptoms caused byMCmediator release. By contrast, in advancedSM, such as aggressiveSM,MCleukemia, andMCsarcoma, intensive (chemo)therapy with or without allogeneic stem cell transplantation has to be considered. In addition, activating mutations inKIT(mostlyKITD816V in adults) are found in most patients withSM, so that targeted therapies aimed at blocking mutantKITvariants or/and downstream signaling pathways are currently being developed. Other targets, such as specific surface antigens expressed on neoplasticMCs, might be considered for the development of future therapies in advancedSM.

Mastocytosis is a term used to denote a group of rare diseases characterized by an abnormal accumulation of neoplastic mast cells in various tissues and organs. In most patients with systemic mastocytosis, neoplastic cells carry activating mutations in KIT. Progress in mastocytosis research has long been hindered by the lack of suitable in vitro models, such as permanent human mast cell lines. In fact, only a few human mast cell lines are available to date: HMC-1, LAD1/2, LUVA, ROSA and MCPV-1. HMC-1 and LAD1/2 cell lines were derived from patients with mast cell leukemia. By contrast, the more recently established LUVA, ROSA and MCPV-1 cell lines were derived from CD34+ cells of non-mastocytosis donors. While some of these cell lines (LAD1/2, LUVA, ROSAKIT WT and MCPV-1) do not harbor KIT mutations, HMC-1 and ROSAKIT D816V cells exhibit activating KIT mutations found in mastocytosis and have thus been used to study disease pathogenesis. In addition, these cell lines are increasingly employed to validate new therapeutic targets and to screen for effects of new targeted drugs. Recently, the ROSAKIT D816V sub-clone has been successfully used to generate a unique in vivo model of advanced mastocytosis by injection into immunocompromised mice. Such model may allow in vivo validation of data obtained in vitro with targeted drugs directed against mastocytosis. In this review, we discuss the major characteristics of all available human mast cell lines, with particular emphasis on the use of HMC-1 and ROSAKIT D816V cells in preclinical therapeutic research in mastocytosis.