# The molecular function of the oncogenic NAB2-STAT6 fusion protein

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2021 · $46,036

## Abstract

Project Summary
 Solitary Fibrous Tumors (SFTs) are a mesenchymal tumor type that affects an estimated 10,000
Americans each year. 10-20% of these tumors become malignant and unresponsive to treatments. The
pathogenesis of SFTs is currently unknown, as there are no recurring mutations in known tumor suppressors
genes or oncogenes. The only recurring mutation identified in SFTs is a gene fusion between NAB2-STAT6 that
results in a fusion protein. NAB2 and STAT6 are both transcription regulators. NAB2 is repressor of early growth
response transcription factors (EGR1/2) and STAT6 is an activator of transcriptional programs in response to
cytokines. Both proteins also contribute to enhancer activation. Despite both proteins' known functions, how
NAB2-STAT6 affects gene expression in SFTs is unknown.
 Using the gene set enrichment analysis (GSEA) of a large microarray data set of SFTs we have found
that the expression of both NAB2 and EGR1 targets were significantly upregulated in SFTs. However, the
expression of STAT6 targets was unchanged. We expressed NAB2-STAT6 and performed ChIP-seq analysis
and found that NAB2-STAT6 localizes to distal active transcriptional enhancers. Lastly, we analyzed RNA-seq
and saw that almost 2000 genes were differentially expressed in Malignant tumors vs Benign tumors including
several genes, which are regulated by well characterized transcriptional enhancers. We hypothesize that NAB2-
STAT6 aberrantly activates EGR1 targets to increase proliferation and highjacks the activity of transcriptional
enhancers to promote malignancy.
 We have generated the intra-chromosomal inversion responsible for NAB2-STAT6 expression in the
benign lung fibroblast IMR90 cell line, which replicates the mesenchymal origin of SFTs using CRISPR-Cas9. In
Aim 1 we will establish NAB2-STAT6’s role in directing aberrant gene expression. We will characterize the
genomic binding profile of NAB2-STAT6 as well as its effect on gene expression and proliferation. In Aim 2 we
will investigate the ability of NAB2-STAT6 to reprogram transcriptional enhancers to promote malignancy. First,
we will develop an inducible NAB2-STAT6 system to measure the ability of NAB2-STAT6 to reprogram
transcriptional enhancers. Then, we will validate our results in primary SFTs and examine differences in
malignant vs benign tumors. Finally, we will examine the ability of transcriptional enhancer changes to affect
gene expression through analysis of RNA-seq of primary SFTs. Overall, these aims will establish the function of
NAB2-STAT6 in promoting tumorigenesis in SFTs

## Key facts

- **NIH application ID:** 10314387
- **Project number:** 1F31CA265257-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Connor Mackenzie Hill
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10314387

## Citation

> US National Institutes of Health, RePORTER application 10314387, The molecular function of the oncogenic NAB2-STAT6 fusion protein (1F31CA265257-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10314387. Licensed CC0.

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