# Cooperative role of TET2 and IDH2 mutations in angioimmunoblastic T-cell lymphomagenesis

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $478,632

## Abstract

Abstract
 Angioimmunoblastic T-cell lymphoma (AITL) is the most common subtype of peripheral T-cell lymphoma
(PTCL) with distinct pathological and clinical characteristics. It is a difficult-to-diagnose and lacks effective
therapies due to poor understanding of the molecular pathogenesis. Using genome-wide gene expression
profiling (GEP), we have defined a robust molecular classifier for accurate diagnosis, identified oncogenic
pathways, discovered its cell-of-origin, and deciphered the role of the tumor milieu in disease prognosis. Using
high-throughput genomic analysis, we also identified frequent mutations in epigenetic regulators (TET2, IDH2
and DNMT3A) and regulators of T-cell activation (RHOA and CD28) in AITL. Co-occurrence of TET2 mutations
with IDH2 mutation (hotspot: arginine-172; IDH2R172) is unique in AITL compared to other hematological
malignancies where they are mutually exclusive, suggesting their cooperative role in T-cell lymphomagenesis.
We have generated unique murine models with conditional loss of Tet2 (Tet2-/-) and double mutant (Tet2-/-
/IDH2R172K) in CD4+ T-cells, and murine lymphomas with follicular helper T-cell (TFH) phenotype were observed.
In addition, we generated several patient-derived xenografts (PDX) of AITL with IDH2R172 and/or TET2 mutations.
We hypothesize that TET2 deficiency in T cells alters the DNA methylation profile leading to an altered
genetic program favoring TFH cell differentiation and clonal expansion, facilitating transformation with
subsequent hits, including IDH2R172 mutation, which will further alter the epigenome and oncogenic
pathways in TFH -cell transformation. We will define the precise role of these genetic lesions in T-cell
differentiation and in AITL pathogenesis. We also edited normal human CD4+ T-cells using CRISPR/CAS9 to
generate TET2-/- T-cells for functional analysis and cross-validation of murine models. SinceTET2 mutations are in
hematopoietic stem/progenitor cells (HSPC) in some AITLs, interactions between TET2 deficient T- and stromal
cells during lymphomagenesis will be explored. We will test the efficacy of therapeutic interventions, including
demethylating agents for TET2 deficiency and IDH2 inhibitors and/or glutamine depletion for TET2/IDH2 double
mutant tumors in murine models and PDX of AITL. To accomplish the objective, three aims are planned:
Specific Aim 1: To determine the mechanisms by which Tet2 deficiency mediates T-cell transformation and the
role of Tet2 mutation in stromal cells in lymphomagenesis.
Specific Aim 2: To delineate the mechanisms of combined Tet2 and IDH2R172K mutations in AITL pathogenesis.
Specific Aim 3: To evaluate therapies targeting oncogenic mechanisms mediated by Tet2 and IDH2R172
mutations.
 Our long-term research goal is to define the pathobiology of AITL, through integrated functional epigenomic
approaches using in vitro modified human T-cells, patient samples and relevant murine models, thus identifying
promising novel targets for trea...

## Key facts

- **NIH application ID:** 10453656
- **Project number:** 5R01CA251412-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Wing C. Chan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $478,632
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10453656

## Citation

> US National Institutes of Health, RePORTER application 10453656, Cooperative role of TET2 and IDH2 mutations in angioimmunoblastic T-cell lymphomagenesis (5R01CA251412-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10453656. Licensed CC0.

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