# Project 3:  Identifying transcriptional driver genes and targeting transcription in TSC

> **NIH NIH P01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $492,594

## Abstract

Program Director/Principal Investigator (Last, First, Middle): Kwiatkowski, David J. et. al., Project 3
Abstract
In this project, we will characterize transcriptional and epigenetic events in TSC hamartomas that are required
to enable tumor growth in the presence of two hit loss of TSC1/TSC2, and consequent downstream activation
of mTORC1. Because we have recently shown that TSC hamartomas display bi-allelic loss of TSC1/TSC2
alone, without accompanying oncogene activation, we hypothesize that the core transcriptional regulatory
circuitry causally contributes to TSC tumor growth and drives particular therapeutic vulnerabilities. Using
H3K27ac ChIP-Seq and RNA-Seq data from AML, we have identified several transcription factors including
MITF as relatively highly expressed and highly marked with H3K27ac, suggesting that these transcription
factors are part of the core transcriptional regulatory circuitry of AML. Furthermore, the CDK7-targeted
transcriptional inhibitor THZ1 causes growth inhibition and apoptosis in a TSC2-null AML cell line, as well as in
TSC1-null human bladder cancer cell lines, both in vitro and in vivo, suggesting that transcription overall is a
key dependency in TSC null tumors. Our Specific Aims are: 1) To characterize MITF as a transcriptional driver
and therapeutic target in AML, identifying downstream targets of MITF that may be targeted; 2) To analyze the
epigenetic landscape and core transcriptional regulatory circuitry in TSC-related hamartomas, thereby enabling
identification of the master transcription factors that drive development of these tumors; and 3) To target
transcription in TSC tumors and cancers with TSC1/TSC2 loss using THZ1 and other CDK7 inhibitors.

## Key facts

- **NIH application ID:** 10221615
- **Project number:** 5P01CA120964-14
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** David J. Kwiatkowski
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $492,594
- **Award type:** 5
- **Project period:** 2006-12-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10221615

## Citation

> US National Institutes of Health, RePORTER application 10221615, Project 3:  Identifying transcriptional driver genes and targeting transcription in TSC (5P01CA120964-14). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10221615. Licensed CC0.

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