# Molecular Pathogenesis of Two Newly Defined Major Subgroups of PTCL

> **NIH NIH P01** · MAYO CLINIC ARIZONA · 2020 · $403,141

## Abstract

Peripheral T-cell Lymphoma (PTCL) encompasses a heterogonous group of clinically aggressive entities.
Using current diagnostic approaches, more than a third cannot be classified and are designated as PTCL-not
otherwise specified (PTCL-NOS). Using gene expression profiling (GEP), we delineated two novel major
molecular subgroups in PTCL-NOS with distinct clinical and biological features. The first (PTCL-GATA3) is
characterized by high expression of GATA3, a master regulator of T helper2 (TH2) differentiation and its target
genes, whereas the second (PTCL-TBX21) is characterized by high expression of TBX21, master regulator of
TH1 differentiation and its target genes, with the former showing significantly worse outcome. Preliminary
genetic characterizations showed distinct patterns of chromosomal copy number abnormalities (CNAs)
associated with significant enrichment of distinct oncogenic pathways. The long-term goal of the research is to
define the mechanisms that determine the biology of these subgroups with the intention of identifying new
targets and strategies for effective treatment, with special emphasis on the PTCL-GATA3 subgroup. This goal
will be accomplished through three Specific Aims: (1) to determine the mutational landscape of the PTCL-
GATA3 and PTCL-TBX21 subgroups. We hypothesize that deciphering the genetic mutational landscape of
PTCL-GATA3 and PTCL-TBX21 will delineate the mechanistic basis of the differences in biology and clinical-
outcome. We will perform whole exome- and RNA-sequencing (WES and RNA-seq) analysis on a well-defined
cohort of PTCLs. A targeted capture panel will be established based on WES data to further determine the
mutational incidence using formalin-fixed paraffin-embedded tissue (FFPET) in a large PTCL cohort including
relapsed/refractory PTCL; (2) to delineate the role of combined PTEN and p53 loss in the pathobiology of the
PTCL-GATA3 subgroup. We previously identified frequent co-occurrence of deletions of genomic loci
encompassing pten and p53 in the PTCL-GATA3 subgroup but not in the PTCL-TBX21 subgroup. These
genetic lesions may have functional consequences other than their canonical role in regulating the
phosphatidylinositol 3-kinase (PI3K) pathway and genomic integrity. We hypothesize that pten and p53 loss
cooperates in the oncogenic transformation of T-cells partly through deregulation of T cell differentiation. We
will use both murine models and genetically modified human T-cells for this study; (3) to evaluate treatments
targeting activated oncogenic pathways in the PTCL-GATA3 subgroup. No representative cell lines or animal
models of poorest prognosis, PTCL-GATA3, subgroup are currently available. We hypothesize that well
characterized PTCL PDTX models can serve as pre-clinical models for evaluating the efficacy of novel drugs in
cases with dual pten/p53 loss. This Project will use Pathology Core 1, Biostatistics/Bioinformatics Core 4,
Pre-Clinical Models and Therapeutics Core 3, and Functi...

## Key facts

- **NIH application ID:** 10013191
- **Project number:** 5P01CA229100-03
- **Recipient organization:** MAYO CLINIC ARIZONA
- **Principal Investigator:** Javeed Iqbal
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $403,141
- **Award type:** 5
- **Project period:** 2018-09-19 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10013191

## Citation

> US National Institutes of Health, RePORTER application 10013191, Molecular Pathogenesis of Two Newly Defined Major Subgroups of PTCL (5P01CA229100-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10013191. Licensed CC0.

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