# Mechanistic Determinants of Follicular-Helper T-cell Lymphomagenesis

> **NIH NIH K08** · DANA-FARBER CANCER INST · 2021 · $250,577

## Abstract

Project Summary/Abstract
Outcomes among patients with Nodal Lymphomas of Follicular-Helper T cell (TFH) origin are poor, with
overall survival rates of <35% at 5 years. These lymphomas are characterized by the recurrent hotspot
RHOA G17V and TET2 loss-of-function (LOF) mutations. The causative molecular contributions of
these mutations to TFH lymphomagenesis remain undefined. Rho family proteins are molecular
switches that are active when bound to GTP and inactive when bound to GDP. The G17V mutation
locks RhoA in an inactive state that has dominant negative and likely neomorphic function through
sequestration of multi-substrate binding partners. TET2 LOF mutations are predicted to cause
increased 5' methylation (5-mC) and decreased 5' hydroxymethylation (5-hmC) of DNA cytosines, both
of which are predicted to result in diminished expression from affected genetic loci. These inactivating
properties make these mutations difficult to target. Recently we and others have determined that RHOA
G17V expression causes increased signaling through the Akt/mTOR pathway during T-cell receptor
(TCR) and co-stimulatory pathway stimulation. We hypothesize that RhoAG17V-mediated disruption
of signaling through multi-substrate small GTPase regulatory proteins combined with gene expression
and epigenetic aberrancies caused by TET2 loss drive lymphomagenesis in T cells. We will test this
with two specific aims. 1. Determine the molecular intermediaries of RhoA G17V-mediated TCR and
co-stimulatory receptor dysfunction. We will determine direct binding partners of RhoA G17V and
define how they modulate TCR and co-stimulatory pathways to promote lymphomagenesis. 2.
Determine the epigenetic and transcriptional aberrancies mediated by TET2 loss in T cells. We will
use a unique Nodal TFH lymphoma cell line to define the epigenetic modifications associated with TET2
loss and to determine whether genes that are silenced by these mutations can act as tumor
suppressors. There are no current therapies that directly target these mutations, and thus, these
studies serve an unmet need for these diseases. Dr. Ng has outlined a five-year development plan to
achieve his goal of becoming an independent investigator in translational cancer research. He has
assembled an advisory committee of internationally recognized experts in antigen-receptor signaling,
malignant T-cell, and lymphoma biology. He has enlisted collaborators who are experts in epigenetics
and computational biology to provide experimental advice and for specific training in the field. Dana-
Farber Cancer Institute is the ideal environment for completion of his scientific and career goals given
its outstanding research community and substantial record for training independent physician-
scientists.

## Key facts

- **NIH application ID:** 10166804
- **Project number:** 5K08CA241089-03
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** SAMUEL YAO-MING NG
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $250,577
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166804

## Citation

> US National Institutes of Health, RePORTER application 10166804, Mechanistic Determinants of Follicular-Helper T-cell Lymphomagenesis (5K08CA241089-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10166804. Licensed CC0.

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