# Function and Mechanism of TET Regulation of Tumor Immunity

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $319,436

## Abstract

Project Abstract
Nearly half of newly discovered cancer driver genes discovered by the cancer genomic studies encode proteins
involved in histone or DNA modification, including the TET family of DNA dioxygenases. Loss-of-function
mutations in TET genes occur early and frequently in human hematopoietic malignancy. Mutations in TET genes,
however, are uncommon in solid tumors. Instead, TET activity is significantly reduced in different types of human
tumors. We do not know the significance of decreased TET activity in solid tumors. In this study, we hypothesize
that TET has a previously unrecognized key function in both the JAK-STAT and NF-κ pathways. Inactivation of
TET in results in chronic tumor-promoting inflammation and escape from anti-tumor immunity. Thus, stimulating
TET activity represents a viable opportunity to enhance antitumor immunity and to improve immunotherapy. We
will test this hypothesis by defining the following aspects of TET2 activity: The function and mechanism of
TET2 in the JAK-STAT pathway and in tumor immunity (Aim 1); The regulation of TET2 and tumor
immunity by reversible monoubiquitylation (Aim 2); and The catalytically independent function and
mechanism of TET2 in tumor suppression (Aim 3).
 During the past funding period, we have made the following discoveries that significantly affect the TET
field and that form the foundation for this investigation: (1) Multiple oncometabolites produced or accumulated by
mutations in different metabolic enzymes act as antagonists α-ketoglutarate (αKG) and inhibit multiple αKG-
dependent enzymes, including TET enzymes. (2) TET activity is dynamically regulated in vivo. (3) Development
of solid tumors of many different types is associated with a substantial decrease in TET activity. (4) TET is
reversibly monoubiquitylated by CRL4VprBP E3 ligase and UPS15 deubiquitylase, enhancing and impairing TET
activity, respectively. This regulation is disrupted by multiple recurrent tumor-derived mutations in TET2. (5) HIV
protein Vpr reprograms CRL4VprBP E3 ligase to catalyze polyubiquitylation and degradation of TET proteins to
sustain the expression of pro-inflammatory cytokine and promote HIV pathogenesis. (6) Multiple sequence-
specific transcription factors (TFs) recruit TET2 to their target genes, including members of NF-κB and STAT
families. (7) Loss of TET2 function in tumors impairs interferon signaling, chemokine production, and T cell
infiltration, and confers resistance to tumor immunity and immunotherapy.
 This investigation is built on our pioneering and extensive study of the then newly discovered TET
enzymes. It will investigate a novel aspect of cytokine signaling and tumor immunity regulation—by TET-
mediated DNA demethylation. It will use newly developed technology and mouse strains to determine how TET
proteins regulate gene expression by catalytically-dependent and -independent mechanisms. It will explore a
novel regulation of TET by reversible monoubiquitylation and the th...

## Key facts

- **NIH application ID:** 10020932
- **Project number:** 5R01CA163834-07
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** ALBERT Sidney BALDWIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $319,436
- **Award type:** 5
- **Project period:** 2012-03-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020932

## Citation

> US National Institutes of Health, RePORTER application 10020932, Function and Mechanism of TET Regulation of Tumor Immunity (5R01CA163834-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10020932. Licensed CC0.

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