# Targeting Metabolic Liabilities of Leukemia-Initiating Cells

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $326,903

## Abstract

PROJECT SUMMARY
The functional relationship between epigenetics and metabolism in cancer progression has not been carefully
examined. Many epigenetic enzymes catalyzing DNA or histone modifications are susceptible to changes in
co-substrates of metabolism, but little is known about whether and how altered epigenetics influences cellular
metabolism during cancer progression. Mutations of EZH2, the histone H3 lysine 27 methyltransferase, are
frequently found in myeloid malignancies and correlate with poor prognosis. We recently developed a new
mouse model of myeloid neoplasms by inactivation of EZH2 and activation of oncogenic NRas (G12D). While
G12D alone led to an indolent myeloproliferation, EZH2 inactivation markedly accelerated disease progression
resulting in myelofibrosis, leukemic transformation and mortality. With this model that faithfully recapitulates
leukemia progression, we unexpectedly identified branched-chain amino acid (BCAA) metabolism as the most
significantly upregulated metabolic pathway in EZH2-deficient leukemia-initiating cells (LICs). BCAT1, the first
enzyme catalyzing BCAA transamination, is repressed by EZH2 in hematopoiesis and aberrantly activated in
EZH2-deficient myeloid neoplasms in mice and humans. Increased BCAT1 promotes BCAA production in
LICs, resulting in activated mTOR signaling. Genetic and pharmacological inhibition of BCAT1 selectively
impairs EZH2-deficient LICs and constitutes a metabolic vulnerability. These findings for the first time connect
dysregulation of EZH2 with altered metabolic pathways in cancer progression. The objective of this project is to
elucidate the causal mechanisms controlling metabolic liabilities of LICs by focusing on the role of BCAA
metabolism in EZH2-deficient myeloid neoplasms. The central hypothesis is that EZH2 deficiency induces
metabolic rewiring by activating BCAT1 and BCAA metabolism to create a metabolic dependency for LICs, and
that inhibition of BCAT1 will selectively eradicate LICs by disabling the metabolic liability of EZH2-deficient
LICs. This hypothesis has been formulated on the basis of our preliminary studies using an in vivo model of
leukemia progression and a newly discovered molecular link between altered epigenetics and metabolism.
Guided by these preliminary data, this hypothesis will be tested by three specific aims: 1) Define the functional
role of BCAT1 in EZH2-deficiency-induced myeloid neoplasms in vivo using BCAT1 knockout and inducible
expression mouse models. 2) Determine the mechanisms by which EZH2-deficient LICs exhibit a metabolic
dependency on BCAA metabolism. 3) Determine the effects of targeting BCAA metabolism in human AML
stem cells using genetic, pharmacological and dietary manipulations. Together these studies will not only
validate a selective metabolic liability for EZH2-mutant myeloid neoplasms, but also uncover new pathways
that can be exploited to selectively eradicate LICs. Such results are expected to advance our mechanistic
und...

## Key facts

- **NIH application ID:** 9854905
- **Project number:** 5R01CA230631-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Jian Xu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $326,903
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854905

## Citation

> US National Institutes of Health, RePORTER application 9854905, Targeting Metabolic Liabilities of Leukemia-Initiating Cells (5R01CA230631-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9854905. Licensed CC0.

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