# The Biology of Mutant STAT6 in Follicular Lymphoma

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $339,008

## Abstract

Follicular lymphoma (FL) is the second most common non-Hodgkin's lymphoma (NHL) in the US, with over
100,000 patients living with the disease. While survival rates at 10 years have improved, almost all patients with
FL receive multiple chemo- or immunotherapies over their lifetime and most eventually relapse and progress.
There exists no highly effective targeted therapy for FL and the standard of care for FL patients remains largely
based on chemoimmunotherapy. New drugs like the BTK inhibitor ibrutinib and the PIK3CD/PI3Kδ inhibitor
idealisib have improved the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL).
However, these drugs are less effective in FL or are linked to serious side effects.
 Over the last eight years we have contributed to the discovery and initial functional characterization of
recurrent mutations in FL, including in the SWI/SNF component ARID1A, linker histones (HIST1H1 B-E), IRF8,
the mTOR regulator RRAGC, various components of the autophagy and mTOR regulator vATPase (ATP6V1B2,
VMA21) and STAT6. One of the important genes that emerged from our efforts is Signal Transducer and
Activator of Transcription (STAT6), which is mutated in 11-23% of all FL and transformed FL (tFL). Frequent
mutations in STAT6 have also been described in primary mediastinal B cell lymphoma (PMBCL), Hodgkin's
lymphoma (HL) and diffuse large B cell lymphoma (DLBCL). STAT6 is part of the IL-4/JAK/STAT6 survival axis
of B cells, which is also activated by elevated IL-4 levels present in FL LNs. The FL-associated mutations in
STAT6 target amino acid hotspots, which are located in the STAT6 DNA binding domain. We have demonstrated
that mutated STAT6 proteins result in the hyper activation of the expression of known STAT6 target genes (e.g.
FCER2, CISH, CCL17, NFIL3). The identification of these gain-of-function properties changed the prevailing
view of lymphoma-associated STAT6 mutations, which previously were believed to be hypomorphs.
 There remain however important unanswered questions pertaining to the molecular properties and functional
consequences of mutated (MUT) STAT6 in lymphoma that are the focus of this proposal. These include the
delineation of genome-wide binding sites of MUT as compared with WT STAT6 in B cells and the complete
characterization of the genes that are transcriptionally regulated by MUT STAT6. Furthermore, the properties
and biological consequences of the transcriptional programs that are activated or repressed by STAT6 in FL B
cells or normal germinal center B cells are largely unknown. There is also untapped potential for the future
targeting of the IL-4/JAK/STAT6 axis in FL and our proposed studies aim at providing the rationale to inform
such studies. Finally, we will explore the interactions between STAT6 MUT FL B cells and the FL lymphnode
resident microenvironment, especially with regards to T cell subsets.

## Key facts

- **NIH application ID:** 10896187
- **Project number:** 5R01CA260677-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Sami Nimer Malek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $339,008
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896187

## Citation

> US National Institutes of Health, RePORTER application 10896187, The Biology of Mutant STAT6 in Follicular Lymphoma (5R01CA260677-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10896187. Licensed CC0.

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