Defining the Biological and Mechanistic Implications of XPO1 Mutations in Hematologic Malignancies

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Candidate: Justin Taylor is an Instructor in Medicine at Memorial Sloan Kettering Cancer Center and Attending on the Leukemia Service at Memorial Hospital. He has been working with his proposed K08 mentor, Dr. Omar Abdel-Wahab, to learn about targeting splicing factor mutant leukemias in translational preclinical models and now has begun independent work to discover the role of XPO1 hotspot mutations in hematologic malignancies as a potential therapeutic target. His goal is to develop an independent research program over the next 5 years and have an independent laboratory doing translational hematologic malignancies research. Career Development Plan: Dr. Taylor has strategically planned to address the necessary training and mentoring that will be required for his successful career transition to independence over the next few years through select coursework and a robust mentoring plan. He has also organized an advisory committee composed not only of leaders in the field but also those able to directly impact his career advancement. This will not only ensure that Dr. Taylor's research project progresses as planned, but also that his progress is recognized by promotion and support in garnering independent research funding. He has a very exciting research project that is sufficiently different from his mentor's research to avoid competition or overlap. Research Plan: Large discovery sequencing projects of cancer sub-types, such as The Cancer Genome Atlas, have identified a multitude of novel recurrent mutations in protein coding genes. The ultimate goal of these sequencing efforts is to lead to improved therapies for patients with cancer and will require understanding how these mutations mechanistically contribute to carcinogenesis. However, even when the function of a gene is known, the biological effect of the mutation cannot always be inferred from the coding sequence. In this proposal, we plan to discover the biological relevance of somatic mutations in the nuclear transport protein XPO1. Somatic mutations in XPO1 have been demonstrated in solid and hematologic malignancies, including ~10% of cases of chronic lymphocytic leukemia and 25% of cases of primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma. Selective inhibition of nuclear export by inhibiting XPO1 has been utilized as an antineoplastic agent in current Phase I/II clinical trials. Yet, despite recognition of XPO1 as a potential driver of cancer, there has been no direct demonstration of the oncogenic potential of somatic mutations in XPO1. We plan to explore the effects of these mutations by using isogenic cell lines, genetically engineered mouse models and human tissues. Furthermore, since XPO1 is a nuclear exporter, we will study the effect of these genetic alterations on protein subcellular localization. Lastly, we aim to determine the effects of XPO1 mutations on response to XPO1 inhibitors currently in development. The end goal of this research will be to discover the biological and mechanistic implications of XPO1 mutations in order to develop rational and informed targeted therapies to treat these cancers for which there is still clinical need.