Project Summary Activating Notch mutations are found in both human T cell acute lymphoblastic leukemia cases (T-ALL) and B cell leukemias/lymphomas including Mantle Cell Lymphoma (MCL). A direct transcriptional target of Notch in both malignancies is the proto-oncogene Myc, which is the most frequently amplified oncogene across a wide range of malignancies as it has critical roles in gene transcription, metabolism, cell proliferation and survival. In the proposed work, we will characterize Myc transcriptional regulation in both T-ALL and MCL. We previously identified a distal (1.3 Mb 3' to the promoter) T cell specific Myc enhancer region termed the Notch-Dependent Myc Enhancer (NDME), that is active in a reporter assay and loops to the Myc promoter in mouse and human T-ALL cells. At least four T cell transcription factors bind in this region, however, their role in activating the NDME is unknown. Previous work from our lab showed that T-ALL cells created to be resistant to Notch inhibition maintain Myc expression through a switch in enhancer usage to another region, termed the Brd4- Dependent Myc Enhancer (BDME). A potential treatment for T-ALL is the BET family inhibitor JQ1, which has already proved efficacious in AML. We generated JQ1-resistant human T-ALL cells that maintain MYC expression. Unlike the T cell NDME, the B cell NDME is located ~500 kb 5' to the Myc promoter and surrounded by B cell specific transcription factors. The goal of this proposal is to understand Notch-dependent Myc regulation in both T-ALL and MCL. In particular, we will determine how Notch regulates Myc enhancer states in T-ALL and MCL and identify factors that cooperate with Notch to ?set-up? and maintain the T cell and B cell NDMEs. In addition to elucidating the function of these enhancers, we will determine how Myc enhancer states dictate drug sensitivity and resistance in T-ALL cells. Together, This work will provide critical insights into the mechanisms of Myc regulation in leukemia and lymphoma and may identify novel targets for treating both de novo and refractory T-ALL and MCL. !