Adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary glands. Over 60% of the ACC patients succumb to the disease as a result of the persistent slow growth, high recurrence rates and propensity to distant metastasis. During the past decades little progress has been made in improving therapies to treat ACC patients, primarily due to the limited knowledge of the genetic alterations involved in ACC development and the lack of relevant experimental models for the disease. The recent discovery of the MYB- NFIB gene fusion in human ACCs has changed this outlook and stimulated new avenues of research that are expected to lead to novel and more effective therapeutic options for ACC patients. Our collaborative studies with Dr. Adel El-Naggar in MD Anderson, identified MYB-NFIB fusions in approximately 40% of the human salivary ACCs. In addition, we observed MYB overexpression in most of the fusion-positive tumors and over half of the ACCs in which the MYB gene was intact. Notably, recent exome sequencing of salivary ACCs confirmed the high rates of MYB alterations and the low prevalence of mutations in other oncogenes or tumor suppressor genes, further reinforcing the notion that salivary ACC is a malignancy driven by alterations in the MYB gene. Based on these clinical observations, in this proposal we will test the hypothesis that MYB overexpression, as part of the MYB-NFIB fusion or in the full-length form, is a primary oncogenic event in ACC development. To test this hypothesis, in Specific Aim 1 we will determine the oncogenic potential of MYB and MYB-NFIB in transgenic mice in which the MYB variants will be overexpressed exclusively in the salivary glands, using an inducible system optimized in our laboratory. To maximize the potential of these mouse models, a reversible inducible system will be generated to induce MYB and MYB-NFIB in salivary glands. Thus, these mice will allow us to determine whether suppression of the MYB or MYB-NFIB functions can promote regression of established tumors. These studies will provide the experimental support for the generation of new therapies designed to inactivate the oncogenic function of MYB or MYB-NFIB fusions to treat patients with ACC. In Specific Aim 2 we will identify MYB and MYB-NFIB target genes that contribute to their oncogenic potential and will determine whether MYB and MYB-NFIB regulate the expression of common and/or distinct targets genes in salivary glands. This analysis will uncover MYB-regulated genes with potential applications to targeted therapy for salivary ACC and will determine the potential of MYB profiling to personalize ACC treatment.