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

> **NIH NIH P01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $741,557

## Abstract

Project 3: Abstract
In this project, we will examine the transcription factors and expression pathways that drive tumor development
in tuberous sclerosis complex (TSC). We have published already that transcription is a key dependence for
TSC tumors, and that MITF is a driver transcription factor for angiomyolipoma (AMLK) development. In addition,
we have recently generated a new model of TSC renal AML by inducing renal differentiation in TSC2-/- human
induced pleuripotent stem cells (hIPSCs) to generate renal organoids. A major cell subset of TSC2-/- renal
organoids have an AML expression phenotype in contrast to control renal-differentiated hIPSCs. In separate
studies, we have used single cell RNA sequencing (scRNA-Seq) to characterize the composition of AML at
high resolution, and have confirmed the importance of MITF-driven transcription in AML cells. In the current
proposal, we will examine the JUN-AXL pathway in TSC tumor development, which leads to a novel kinase
inhibitor sensitivity. Using a Drosophila model, we will dissect in further detail how mTORC1 regulates Mitf
activity, and then translate key findings to mammalian cells. Last, we will use the TSC2-/- hiPSC renal
organoid model to identify the transcriptional circuitry required for AML development, using scRNA-Seq,
scATAC-Seq, and scChIP-Seq for H3K27ac and MITF. We will also determine the entire panel of transcription
factors required for AML cell development using Perturb-Seq applied to the TSC2-/- hiPSC renal organoid
model. Expected health-related outcomes include identification of multiple potential therapeutic approaches
for both TSC patients and cancers with TSC2/TSC1 mutations.

## Key facts

- **NIH application ID:** 10931466
- **Project number:** 5P01CA120964-17
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** David J. Kwiatkowski
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $741,557
- **Award type:** 5
- **Project period:** 2007-04-24 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931466

## Citation

> US National Institutes of Health, RePORTER application 10931466, Project 3:  Identifying transcriptional driver genes and targeting transcription in TSC (5P01CA120964-17). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10931466. Licensed CC0.

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