The Role of ZEB1 Mutations in Cutaneous T Cell Lymphoma

Project: Research project

Description

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. During my career, 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 CTCLs. 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).
StatusActive
Effective start/end date12/8/156/30/20

Funding

  • National Cancer Institute (5K08CA191019-06)

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Cutaneous T-Cell Lymphoma
Mutation
Neoplasms
T-Lymphocytes
Peripheral T-Cell Lymphoma
Exome
Skin
Inborn Genetic Diseases
Germ-Line Mutation
Homeobox Genes
Zinc Fingers
Non-Hodgkin's Lymphoma
Immunosuppression
Cause of Death
Immune System
Lymphoma
Transcription Factors
Clone Cells
Lymph Nodes
Binding Sites