Despite advances in the clinical treatment of B-cell lymphoma, patients with certain high-risk genetic lesions continue to have poor outcomes with current therapies. Recurrent gain-of-function mutations in genes encoding Notch receptors are associated with aggressive disease and decreased survival in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). The oncogenic effects of altered Notch signaling are likely mediated through activation of gene regulatory targets by the Notch transcription factor complex, but the specific targets of altered Notch signaling in B-cell lymphoma are largely unknown, limiting our ability to devise rational treatment strategies for these patients. I recently used genome-wide epigenetic profiling to identify lymphoma subtype-specific enhancers and enhancer-associated genomic rearrangements in primary tumor samples from diverse B-cell lymphoma subtypes (Cancer Discovery, 2015), linking transcription factor-mediated enhancer activation to specific oncogene programs. I will extend this approach in primary CLL and MCL specimens, as well as physiologically relevant in vitro and in vivo models, to uncover the specific gene targets of Notch signaling and identify cooperating pathways. I will use this improved biological understanding of the role of Notch in B-cell lymphomas to design and pre-clinically test novel strategies for the treatment of Notch-driven lymphomas. I am a hematopathologist with a strong research interest in the role of altered transcriptional regulatory genes in the biology of B-cell lymphoma. My primary career objective in the coming years is to obtain a tenure-track position at an academic medical center as a research laboratory Principal Investigator. I am seeking K08 support for mentored research in the laboratory of Dr. Bradley Bernstein at Massachusetts General Hospital / Broad Institute, with co-mentorship from Dr. Jon Aster at Brigham and Women?s Hospital and Dana-Farber Cancer Institute. A K08 award would give me protected time to advance my research program, to develop additional skills in the biological analysis of genome-wide data sets, and to pursue specialized training and experience in the use of physiologically relevant mouse models for the study of lymphoma. I will devote at least 80% of my time to a focused research investigation into the mechanisms of Notch signaling and transcriptional regulation in B cell lymphomas, with up to 20% of my time devoted to the clinical diagnosis of hematological malignancies, as well as teaching and training pursuits. Massachusetts General Hospital, Broad Institute of MIT and Harvard University, Brigham and Women?s Hospital, and Dana-Farber Cancer Institute are institutions of international renown in the fields of biomedical research and research training, and host the laboratories of many highly accomplished experts in lymphoid malignancy, transcriptional and epigenetic regulation, and experimental therapeutics. The Department of Pathology at Massachusetts General Hospital has a distinguished history in the training of independent cancer researchers, and the development and use of advanced molecular tools for cancer diagnosis. I have assembled an advisory team of local experts in areas of importance to my project, consisting of Dr. Catherine Wu, Dr. X. Shirley Liu, and Dr. David Weinstock, who will advise me in the conduct of this research, as well as my career development. I have initiated collaborations with other academic physicians and scientists who will provide specific resources and guidance to advance my investigations (Dr. Irwin Bernstein, in vitro modeling of Notch activation, Dr. A. John Iafrate, molecular diagnostics and biomarkers, and Dr.
Ephr aim Hochberg, clinical therapeutic research in lymphoma). I have formulated a structured career development plan that includes training and mentorship in laboratory management, scientific leadership, research communication, grant writing, and other critical career skills. Together, the elements of this proposal will provide me with the experience, training, and mentorship needed to become a successful independent physician-scientist with a clinical focus on lymphoma diagnostics, and a productive research career in basic and translational lymphoma biology.
Despite improved treatments for mantle cell lymphoma and chronic lymphocytic leukemia, patients with gain- of-function mutations of genes in the Notch signaling pathway continue to have poor outcomes. This research proposal will investigate the cellular pathways that are driven by aberrant Notch signaling in B-cell lymphoma. By understanding the relationship between Notch signaling and other oncogenic pathways in these cancers, we will seek to develop new therapeutic strategies, and ultimately lead to advances that improve patient survival.
|Ryan, Russell J H; Petrovic, Jelena; Rausch, Dylan M et al. (2017) A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas. Cell Rep 21:784-797|