Project Summary
Neurofibromatosis type 2 (NF2) is an inherited disorder caused by germ line mutations of the NF2 tumor
suppressor gene and is characterized by development of schwannomas of the VIIIth cranial nerve. Merlin, the
product of the NF2 gene, is also inactivated to a significant extent in sporadic schwannomas, meningioma,
ependymoma and mesothelioma. In spite of progress made in the understanding of the disease over the past
several years, this has not yet translated into therapies. Thus, there is an urgent and unmet need to develop
therapeutic options for NF2 patients. At a molecular level, Merlin has been shown to function as a key regulator
of multiple signal transduction pathways including those regulated by small G-proteins and the Hippo/YAP
pathway.
In an effort to identify therapeutic vulnerabilities in NF2-deficient tumors, we assessed the activity of the BET
(Bromodomain and Extra-Terminal domain) protein inhibitors NF2-null Schwann cells. The BET proteins are
characterized by the presence of two tandem bromodomains and an extra-terminal domain. The bromodomains
can specifically bind acetylated lysine residues on histones, serving as epigenetic readers that decipher the
histone acetylation code. Our preliminary data indicate that BET inhibition suppresses the proliferation of NF2-
null Schwann and schwannoma cells in culture and tumor growth in vivo, and that this is mediated through
inhibition of bromodomain protein 4 (BRD4). Preliminary data indicates that the effects of BRD4 are mediated to
a significant extent via regulation of YAP. Importantly, we recently demonstrated that YAP is required for the
accelerated proliferation of NF2-deficient Schwann cells and tumorigenesis. The goals of this proposal are to
identify the essential functions of BET proteins in Schwann cells and determine whether BET inhibition is a
therapeutic approach that should be further developed as a treatment modality for NF2.
