The Role of ZEB1 Mutations in Cutaneous T Cell Lymphoma

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 DESCRIPTION (provided by applicant): The NIH K08 mentored career development award provides the necessary foundation for me to fulfill my long- term career goal of becoming an independently funded translational investigator with a clinical and scientific focus on cutaneous T cell lymphoma (CTCL). CTCL is an incurable non-Hodgkin lymphoma of the skin-homing CD4+ T cell. Patients initially present with lymphoma cells exclusively in the skin; however, as disease progresses, the tumor cells spread to the blood, lymph nodes, and visceral organs. The malignant T cell clone produces cytokines that dramatically alter the immune system; correspondingly, a common cause of death from CTCL is fatal immunosuppression. As an Assistant Professor at Yale, I have focused my clinical efforts on caring for patients with this malignancy. Since cancer is fundamentally a genetic disease, I have focused my laboratory efforts on identifying the genetic basis of CTCL. To our knowledge, I have performed the first exome sequencing of CTCL. Sequencing 40 CTCLs from patients with advanced leukemic disease, we have identified the landscape of cancer promoting mutations with high clarity. In particular, we found that ZEB1 is a critical tumor suppressor in CTCL, subject to loss-of-function mutations in 65% of patients. ZEB1 encodes a zinc finger E-box binding homeobox transcription factor that interestingly has putative binding sites at multiple genes thought to mediate CTCL's distinctive immune phenotype. Highlighting its tumor suppressor function in T cells, 84% of mice with germline mutations in ZEB1 spontaneously develop CD4+ peripheral T cell lymphomas (PTCL). In this proposal, our objectives are to elucidate the role of ZEB1 mutations in promoting the malignant transformation of CD4+ T cells. In Aim 1, we will determine the time of onset of ZEB1 mutations in CTCL by sequencing ZEB1 in early-stage skin-limited CTCL and whole genome sequencing ZEB1 in leukemic CTCL. In Aim 2, we will identify the transcriptional targets of ZEB1 in CTCL, using 1) RNA-Seq to find transcripts that are altered in ZEB1-/- CTCL and 2) ChIP-Seq to identify ZEB1's binding sites in ZEB1-replete CD4+ T cells. In Aim 3, we will isolate the contribution of ZEB1 mutations to lymphomagenesis in vivo by carefully analyzing the phenotypes and transcriptomes of ZEB1-/- murine PTCLs. To achieve the expertise necessary for the successful achievement of the proposed aims, I have committed to a comprehensive training plan utilizing the extensive scientific and clinical resources available in Yale's world-renowned Departments of Genetics, Immunobiology, and Dermatology. I will follow a structured curriculum consisting of seminars and coursework in immunobiology, statistics, and bioinformatics. In addition, I will be closely mentored by a highly qualified primary mentor (Dr. Richard Lifton) and an advisory committee, which was carefully chosen for their proven track record for mentorship and non-overlapping expertise in CTCL, epigenetics, and immunobiology. In sum, this proposal will hopefully elucidate a critical mechanism underlying CTCL pathogenesis while preparing me for a successful independent career as a physician scientist.