Proliferative disorders of mast cells exhibit a range of clinical behavior from benign cutaneous forms to aggressive systemic mastocytosis and mast cell leukemia. While these disorders are rare in people, they are among the most common malignancies in the dog, a circumstance that provides a useful model for an orphan disease. Growth of both normal and neoplastic mast cells is driven by c-kit (CD117), a tyrosine kinase receptor for stem cell factor. Ligand-independent, constitutive activation of c-kit via mutation is a common feature of mastocytic neoplasia. Therefore, tyrosine kinase inhibitors (TKIs) that target c-kit have activity in aggressive mastocytosis in people and in dogs. However, resistance to c-kit targeted TKIs is common in both species, highlighting a need for other therapeutic targets.

Our data indicates that chromatin modification may be important in mast cell biology. Specifically, we have shown that the JmjC domain lysine 36 specific histone H3 demethylase, NDY1/KDM2B, supports the proliferation and immortalization of bone-marrow derived mast cells. It is well known that NDY1/KDM2B is a driver of hematopoietic transformation and is associated with malignant progression in certain solid tumors (breast, pancreatic and urothelial carcinoma). Therefore, we investigated the effects of knockdown of NDY1/KDM2B in neoplastic human and canine mast cells in vitro and in xenografts. Our data demonstrate that this knockdown inhibits proliferation and induces apoptosis in vitro and inhibits tumor growth in vivo. Therefore, targeting therapy of NDY1/KDM2B or downstream effectors in mast cell tumors could be a beneficial addition to the existing therapeutic modalities.

Supported by grants from the Morris Animal Foundation (D14CA) and NIH (R01CA109747).

Citation Format: Parthena Foltopoulou, Raymond Pfau, Monica Betancur-Boissel, Manar AbdelMageed, Philip N. Tsichlis, Elizabeth A. McNiel. Histone demethylase NDY1/KDM2B as a driver of survival and proliferation of normal and neoplastic mast cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3635. doi:10.1158/1538-7445.AM2015-3635