# Mutational cooperativity in TET2-associated hematological malignancies.

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2022 · $335,422

## Abstract

Project Summary/ Abstract
Peripheral T cell lymphoma (PTCL) represents a group of aggressive blood cancers derived from mature T
cells, and remains as a high unmet clinical need with poor prognosis and lack of standards of care and
effective treatment. Recent exome sequencing in PTCL patients has unveiled a frequent co-occurrence of
mutations in an epigenetic modifier (TET2) and a small GTPase (RHOA). This discovery heralds the advent of
a molecular era in the dissection of novel pathogenic mechanisms underlying T cell lymphoma. The PI has
shown that genetic depletion of murine Tet2 alone in blood cells causes biased differentiation of hematopoietic
stem and progenitor cells (HSPCs) toward the myeloid lineage, but is insufficient to cause lymphoid neoplasms.
A second hit, such as RHOA-G17V frequently found in PTCL, is required to promote full-blown malignancies.
To meet the immediate need for animal models of PTCL, The PI has generated a genetically modified rodent
model mimicking the PTCL-associated genotype with genetic lesions in both TET2 and RHOA. This transgenic
mouse model is well suited to study PTCL because it developed T cell lymphoma in peripheral lymphoid
organs and recapitulated hallmark phenotypes as seen in PTCL patients. These exciting findings laid a strong
scientific foundation to hypothesize that: co-existing TET2 and RHOA mutations in CD4 T cells contribute to
the pathogenesis of PTCLs by
(i)
impairing DNA hydroxymethylation and gene transcription to predispose T
cells for pre-malignant status (Aim 1; with a mechanistic emphasis on R-loop accumulation and aberrant RNA
polymerase II pausing in key genes involved in phosphoinositide metabolism), and
(ii)
disrupting the Rho
GTPase signaling to abnormally activate pro-oncogenic pathways for malignant transformation (Aim 2; with a
prioritized focus on the PI3K/Akt signaling). The team has presented compelling evidence in pilot studies that
lends strong support to the central hypotheses and the feasibility of our approach. Technical innovations
include a unique mouse model that reflects the PTCL-associated genotype and disease hallmarks, as well as a
set of novel molecular tools tailored for precise epigenome mapping/editing and optogenetic control of small
GTPase signaling. These tools allow the team to overcome a major impediment to studies of epigenotype-
phenotype causal relations in pre-malignant and malignant T cells. This research is also conceptually
innovative as it introduces a previously underappreciated dimension for studying the epigenetic regulatory
mechanisms, as well as aberrant GTPase signaling, that drive lymphomagenesis. The proposed studies will
likely illuminate how somatic mutations in epigenetic and GTPase signaling pathways cooperatively contribute
to the initiation, transformation and progression of lymphoma. From a translational perspective, the findings
may reveal novel molecular targets and pathways for therapies against lymphoma.

## Key facts

- **NIH application ID:** 10366080
- **Project number:** 5R01CA240258-02
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Yun Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $335,422
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366080

## Citation

> US National Institutes of Health, RePORTER application 10366080, Mutational cooperativity in TET2-associated hematological malignancies. (5R01CA240258-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10366080. Licensed CC0.

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