# Defining clinically relevant transcriptional networks in gastrointestinal stromal tumor

> **NIH NIH K08** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $223,535

## Abstract

Project Summary
Gastrointestinal stromal tumor (GIST) is a common form of soft tissue sarcoma, and our limited ability to predict
the course of metastatic disease or the risk of recurrence following resection creates significant uncertainties in
patient care. These critical unresolved problems underscore the deficit in biological understanding of factors
involved in GIST oncogenesis and clinical behavior. We have previously characterized the enhancer and
transcriptional landscape of GIST, using this information to identify a transcription factor (TF) network with
elements predictive of patient outcomes. Within this network are core TF members present in all GIST subtypes
and responsible for establishing basal GIST transcriptional output. Additional accessory TFs are present in a
disease state-specific manner, being found exclusively in indolent or aggressive disease. Supporting the TF
network, the MOZ histone acetyltransferase complex is uniquely responsible for establishing enhancers in GIST.
Our central hypothesis is that core TFs and the MOZ chromatin regulatory complex generate the GIST
transcriptional program, which is modified by state-specific accessory TFs to instruct disease behavior
and determine clinical outcomes.
 Understanding how core TFs function to control the GIST epigenome, and how accessory TFs modulate
this oncogenic framework, is of chief relevance to understanding the biology of this disease. Aim 1 of this
proposal seeks to characterize how the core TF network members interact with enhancers and other
transcriptional regulators to exert gene regulation. Because defined accessory TFs are expressed exclusively in
a disease state-specific fashion, Aim 2 will determine how these factors modify the core TF network and
influence transcriptional output through genetic disruption, and accessory TF expression in clinical samples will
be used to associate their expression with clinical outcomes. Finally, Aim 3 will define the role of the MOZ
complex, a unique dependency in GIST, in collaborating with TFs to generate the GIST transcriptional state.
These studies will define the transcriptional machinery that underlies GIST, advance our understanding of
molecular determinants of indolent and aggressive disease, and develop a biological framework for novel
approaches to predicting clinical behavior that may impact the care of patients suffering from this disease.
 As a physician-scientist dedicated to understanding and treating sarcoma, my long-term goal is to
develop an independent research program to generate a detailed understanding of GIST biology that will
transform patient care. During my proposed training period, I will perform mentored research in the laboratory of
Dr. Scott Armstrong at DFCI, with supportive co-mentorship from Dr. George Demetri; my outstanding advisory
committee will further guide my research and career development. This mentorship, together with my exceptional
institutional environment, access to superb educat...

## Key facts

- **NIH application ID:** 10752803
- **Project number:** 7K08CA245235-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Matthew Hemming
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $223,535
- **Award type:** 7
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10752803

## Citation

> US National Institutes of Health, RePORTER application 10752803, Defining clinically relevant transcriptional networks in gastrointestinal stromal tumor (7K08CA245235-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10752803. Licensed CC0.

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