# Elucidating transcriptional and epigenetic regulators of aggressive cutaneous T cell lymphoma

> **NIH NIH F31** · NORTHWESTERN UNIVERSITY · 2022 · $41,965

## Abstract

Project Summary/Abstract
Cutaneous T-cell lymphoma (CTCL) is an incurable non-Hodgkin lymphoma of skin homing T cells. Clinical
outcomes of CTCL are highly heterogenous with some patients surviving <6 months and others >10 years in
stage matched patients with advanced disease. The molecular mechanisms that drive heterogeneity of disease
outcomes remain poorly understood. We have employed whole genome sequencing, RNA sequencing, and
functional assays in a large cohort of primary patient samples to understand the genetic basis of CTCLs. We
have identified deletion of PDCD1, a gene encoding the co-inhibitory receptor PD1, as a monogenic driver of
CTCL disease aggression and phenotypes. Analysis of CTCLs in a multi-institutional cohort showed that PD1
deletion predicts a significantly worse overall survival in patients. This is recapitulated in our functional assays
with primary patient samples where CTCLs with PD1 deletion displayed increased proliferation ex vivo. Notably,
PD1 expressing CTCLs had increased expression of co-inhibitory receptors and gene signatures of T cell
exhaustion, a dysfunctional state in T cells that limits effector functions. Interestingly, PD1 appears to drive a
durable exhaustion phenotype that is retained by cells ex vivo even in the absence of ligand, suggesting that
exhausted CTCLs have an epigenetic tumor suppressor program that is lost in PD1 deleted CTCLs. In addition,
our preliminary RNA-seq data identified 60 transcription factors differentially expressed between PD1 expressing
and deleted cohorts of CTCL, many but not all have been implicated in T cell exhaustion from studies with tumor
models. Therefore, in this proposal, we aim to mechanistically dissect the epigenetic and transcriptional
regulation of aggressive phenotypes in PD1-deleted CTCL samples. In Aim 1, we will identify whether
transcription factors upregulated in PD1 expressing CTCLs are necessary or sufficient for in promoting CTCL
exhaustion. In addition, we will also utilize primary patient samples to determine if the reversal of
downregulation/upregulation of transcription factors in each CTCL cohort can reverse or increase exhaustion
phenotypes. In Aim 2, we will elucidate the PD1 dependent epigenetic regulators in primary CTCLs We will
combine epigenetic and transcriptomic data to identify differentially expressed transcription factors in each CTCL
cohort in an unbiased way. My overall career goal is to become a successful, independent research scientist.
The rigorous training plan proposed in this fellowship will allow me to achieve that goal by gaining research skills
and knowledge in cellular immunology, cancer signaling pathways, and epigenetics. I will be mentored by Dr.
Jaehyuk Choi, an expert physician-scientist in CTCL, and Dr. Deyu Fang, a world-renowned T cell biologist, who
have devised a joint training plan to develop all necessary research skills, communication skills and promote my
professional development. This fellowship will broa...

## Key facts

- **NIH application ID:** 10389198
- **Project number:** 1F31CA268839-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Calvin Yuen Yee Law
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $41,965
- **Award type:** 1
- **Project period:** 2022-02-15 → 2024-02-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10389198

## Citation

> US National Institutes of Health, RePORTER application 10389198, Elucidating transcriptional and epigenetic regulators of aggressive cutaneous T cell lymphoma (1F31CA268839-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10389198. Licensed CC0.

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