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 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). 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, epigenetic, 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.

Public Health Relevance

Cutaneous T cell lymphoma (CTCL) is an incurable non-Hodgkin lymphoma of the skin-homing CD4+ T cell. The transcription factor, ZEB1, is a critical tumor suppressor in this disease as it is subject to loss-of-function mutations in 65% of CTCLs. Our objectives are to identify the genes and pathways altered by mutations in ZEB1 with the long-term goal of developing novel therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA191019-04
Application #
9294990
Study Section
Subcommittee I - Transistion to Independence (NCI)
Program Officer
Lim, Susan E
Project Start
2015-12-08
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Dermatology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Zhou, Xiaolong Alan; Louissaint Jr, Abner; Wenzel, Alexander et al. (2018) Genomic Analyses Identify Recurrent Alterations in Immune Evasion Genes in Diffuse Large B-Cell Lymphoma, Leg Type. J Invest Dermatol 138:2365-2376
Park, Joonhee; Yang, Jingyi; Wenzel, Alexander T et al. (2017) Genomic analysis of 220 CTCLs identifies a novel recurrent gain-of-function alteration in RLTPR (p.Q575E). Blood 130:1430-1440
King, Brett; Lee, Alfred Ian; Choi, Jaehyuk (2017) Treatment of Hypereosinophilic Syndrome with Cutaneous Involvement with the JAK Inhibitors Tofacitinib and Ruxolitinib. J Invest Dermatol 137:951-954
Gmyrek, Grzegorz B; Pingel, Jeanette; Choi, Jaehyuk et al. (2017) Functional analysis of acquired CD28 mutations identified in cutaneous T cell lymphoma. Cell Immunol 319:28-34
Bi, Mark; Zhao, Siming; Said, Jonathan W et al. (2016) Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma. Proc Natl Acad Sci U S A 113:2170-5
Goh, Gerald; Walradt, Trent; Markarov, Vladimir et al. (2016) Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy. Oncotarget 7:3403-15
YĆ©lamos, Oriol; Merkel, Emily A; Sholl, Lauren Meldi et al. (2016) Nonoverlapping Clinical and Mutational Patterns in Melanomas from the Female Genital Tract and Atypical Genital Nevi. J Invest Dermatol 136:1858-1865
Walker, Sarah; Wang, Chen; Walradt, Trent et al. (2016) Identification of a gain-of-function STAT3 mutation (p.Y640F) in lymphocytic variant hypereosinophilic syndrome. Blood 127:948-51
Zhang, Xiaoran; Rao, Aparana; Sette, Paola et al. (2016) IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligand expression. Neuro Oncol 18:1402-12