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Haematologica 2018 Volume 103(2):1760-1771
Ferrata Storti Foundation
Preclinical human models and emerging therapeutics for advanced systemic mastocytosis
Michel Arock,1,2 Ghaith Wedeh,1 Gregor Hoermann,3,4 Siham Bibi,1 Cem Akin,5 Barbara Peter,4,6 Karoline V. Gleixner,4,6 Karin Hartmann,7 Joseph H. Butterfield,8 Dean D. Metcalfe9 and Peter Valent4,6
1LBPA CNRS UMR8113, Ecole Normale Supérieure Paris-Saclay, Cachan, France; 2Laboratory of Hematology, Pitié-Salpêtrière Hospital, Paris, France; 3Department of Laboratory Medicine, Medical University of Vienna, Austria; 4Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria; 5Michigan Medicine Allergy Clinic, University of Michigan, Ann Arbor, MI, USA; 6Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria; 7Department of Dermatology, University of Luebeck, Germany; 8Mayo Clinic, Division of Allergic Diseases, Rochester, MN, USA and 9Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD, USA
ABSTRACT
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 sys- temic mastocytosis, the 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. The 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 dis- ease pathogenesis. In addition, these cell lines are increasingly employed to validate new therapeutic targets and to screen for effects of new tar- geted drugs. Recently, the ROSAKIT D816V subclone has been successfully used to generate a unique in vivo model of advanced mastocytosis by injection into immunocompromised mice. Such a 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.
Introduction
Mast cells (MC) are tissue-fixed cells found in all vascularized organs. These cells are involved in a number of physiological processes, such as adaptive and innate immune responses.1 Moreover, MC play a central role in many pathological conditions, including allergic reactions and mastocytosis.2 MC develop from bone marrow CD34+/CD117+ progenitor cells,3 which enter the circulation and migrate into tissues, where they mature into MC in response to their major growth factor, stem cell factor (SCF), the ligand of KIT, also known as CD117. KIT is a transmem- brane receptor with intrinsic tyrosine kinase activity (Figure 1).4 Besides, mature tissue MC express the high affinity receptor for IgE (FcεRI) and can be activated through this receptor during allergic reactions.5
Correspondence:
arock@ens-cachan.fr
Received: May 4, 2018. Accepted: June 27, 2018. Pre-published: July 5, 2018.
doi:10.3324/haematol.2018.195867
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/11/1760
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