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Preclinical models of mastocytosis
LUVA, ROSA and MCPV-1. While none of these cell lines simultaneously expresses the KIT D816V mutant and a functional FcεRI, making them useless for testing MC-sta- bilizing drugs or drugs interfering with FcεRI-induced sig- naling in the context of KIT D816V+ SM, some of these cell lines may qualify as MCL-like since they harbor SM-relat- ed KIT variants and/or other oncogenic molecules relevant to SM. Among all MC lines, HMC-1 cells have been most frequently used, but other more recently established MC lines, such as ROSA and MCPV-1, are now available and are being used in various preclinical studies. For example, these cell lines have been used to analyze in vitro the growth-inhibitory effects of antineoplastic drugs, including various KIT-TKI, on neoplastic MC. However, because neoplastic MC in advanced SM are triggered by KIT-inde- pendent signaling pathways and additional genetic lesions that confer resistance against KIT-TKI, it might be interest- ing to establish in vitro models of multi-mutated neoplastic MC, starting from established human KIT mutant-positive MC lines in which additional lesions, such as the S/A/R
combination of molecular lesions might be introduced. Such multi-mutated neoplastic MC lines should be useful to test combination therapies in vitro, and later in clinical tri- als in patients with advanced SM. With these approaches, new therapeutic concepts should be established in order to improve therapy in advanced SM.
Acknowledgments
The authors would like to thank Dr Patrick T. Gunning (Department of Medical Biophysics, University of Toronto, Ontario, Canada) for kindly providing the STAT-specific inhibitors presented in the manuscript. We also express our deep thanks to Dr Fawzia Louache (Inserm UMRS-1170, CNRS GDR 3697 Micronit, Institut Gustave Roussy, Université Paris- Sud, Université Paris-Saclay, Villejuif, France) for her invalu- able help with the in vivo studies presented in the manuscript. K.H. is supported by a research grant from the German Research Council (DFG; HA 2393/6-1). DM is supported by the DIR, NIAID, and PV is supported by the Austrian Science Fund (FWF) grants F 4701-B20 and F 4704-B20.
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