# Tumor suppressive functions of TET proteins in B cell malignancies: role of G-quadruplex structures

> **NIH NIH K99** · LA JOLLA INSTITUTE FOR IMMUNOLOGY · 2021 · $144,720

## Abstract

Abstract
TET-family of dioxygenases mediate DNA demethylation by sequentially oxidizing 5-methylcytosine (5mC) to 5-
hydroxymethyl- (5hmC), 5-formyl- (5fC) and 5-carboxyl-cytosine (5caC). TET enzymes are required for normal
development and loss-of TET function due to mutations, metabolic reprogramming, hypoxia and other additional
mechanisms occurs frequently in many hematological malignancies and solid tumors. Recent studies have
identified mutations in TET proteins and metabolic enzymes which regulate TET catalytic activity in a large cohort
of patients with Diffuse Large B-cell Lymphoma (DLBCL). However, the clinical significance of these mutations
in DLBCL and the molecular mechanisms through which TET proteins suppress development of malignancies
in general, is not well-understood.
Studies from us and others have highlighted that TET activity is required for differentiation of mature B cells; the
cell-of-origin for DLBCL. To investigate the role of TET loss-of-function in the pathogenesis of DLBCL, I recently
generated mice with B-cell-specific deletion of TET2 and TET3 proteins. Deletion of TET2 and TET3 in mouse
B cells caused development of aggressive lymphomas and rapid mortality. Preliminary analysis of TET-deficient
B cells revealed increased genomic instability and a striking accumulation of unusual secondary DNA structures
called G-quadruplexes (G-quads). The accumulation of G-quads occurred at early stages of B-cell expansion
and was also a feature associated with TET-deficiency in other cellular lineages. G-quad structures have been
linked to genomic instability and transcriptional alterations in cancers but their physiological functions in normal
cells and pathological roles in malignant cells remain poorly understood.
For the studies proposed here, I hypothesize that TET proteins function as tumor suppressors by limiting the
accumulation of G-quad structures. Studies in Aim1 will examine the association of G-quad structures with TET
activity, genomic instability and transcriptional alterations during TET loss-of-function induced
lymphomagenesis. Aim2 will interrogate molecular mechanisms by which TET proteins limit the accumulation of
G-quad structures. Aim3 will focus on delineating mechanisms by which G-quads regulate chromatin structure
and function in normal and malignant B cells. Studies in Aim2 and Aim3 will be performed in R00 phase and will
likely prime the emergence of many new lines of investigations. Together, these studies will use B cells as a
model system to understand the mechanistic basis for the broad tumor suppressive functions of TET proteins
and will reveal novel facets about the biological functions of G-quad structures.
The proposal outlines a specific training plan for the K99 and R00 phases, to acquire the skillset necessary to
perform the proposed studies and successfully transition to an independent position. During this process, I
anticipate to develop an independent line of research through my continue...

## Key facts

- **NIH application ID:** 10125131
- **Project number:** 5K99CA248835-02
- **Recipient organization:** LA JOLLA INSTITUTE FOR IMMUNOLOGY
- **Principal Investigator:** Vipul Shukla
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $144,720
- **Award type:** 5
- **Project period:** 2020-03-10 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125131

## Citation

> US National Institutes of Health, RePORTER application 10125131, Tumor suppressive functions of TET proteins in B cell malignancies: role of G-quadruplex structures (5K99CA248835-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10125131. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*