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Elucidating transcriptional and epigenetic regulators of aggressive cutaneous T cell lymphoma

Award Number: F31CA268839
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/15/2022
PERIOD OF PERFORMANCE END DATE: 02/14/2024

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Elucidating transcriptional and epigenetic regulators of aggressive cutaneous T cell lymphoma - 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 broaden our understanding of CTCL pathogenesis and T cell exhaustion, identify potential novel therapeutic strategies, and provide the necessary foundation for my future career as a research scientist.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$131 )
2025	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	000	2	12/20/2024	NON-COMPETING CONTINUATION	-$131
														Subtotal = -$131

Issue Date FY: 2023 ( Subtotal = $42,907 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	000	2	1/6/2023	NON-COMPETING CONTINUATION	$41,965
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	001	2	7/20/2023	NON-COMPETING CONTINUATION	$942
														Subtotal = $42,907

Issue Date FY: 2022 ( Subtotal = $41,965 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	001	1	2/9/2022	NEW	$0
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	000	1	2/9/2022	NEW	$41,249
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	002	1	8/12/2022	NEW	$716
														Subtotal = $41,965

Grand Total All Awards = $84,741

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Elucidating transcriptional and epigenetic regulators of aggressive cutaneous T cell lymphoma

Award Number: F31CA268839

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/15/2022

PERIOD OF PERFORMANCE END DATE: 02/14/2024

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