# METABOLIC REGULATION IN LEUKEMIA-INITIATING CELLS

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $438,806

## Abstract

AML is the most common acute leukemia in adults, and it appears increasingly with age. Despite overall
improvement in the treatment of leukemia, AML still carries a devastating prognosis for elderly patients (less
than 10% of patients survive for 5 years). Thus, new therapies for AML are necessary. AMPK is a metabolic
regulator that promotes catabolism and inhibits anabolism, thereby maintaining metabolic homeostasis upon
metabolic stress. Using mouse models and AMPK inhibitors, we demonstrated that AMPK inhibition renders
AML sensitive to metabolic stress induced by dietary restriction (Saito et al. Cell Stem Cell. 2015). During this
study, we noticed that AMPK deletion reduces acetyl-coA and histone acetylation in AML (Fig. 2), concomitant
with decreased expression of critical leukemia-promoting genes such as Myc. Importantly, chromatin
immunoprecipitation and sequencing (ChIP-seq) revealed that AMPK deletion reduces the occupancy of
acetylated histones, all of which marks active genes and recruits transcriptional regulators. We thus
hypothesized that AMPK links metabolism to epigenetics in AML by maintaining histone acetylation. In aim 1 we
will determine whether the occupancy of transcriptional regulators in AML is regulated by AMPK. In aim 2, we
will determine how metabolites and the metabolic enzymes that produces acetyl-coA regulate histone
acetylation. In aim 3, we will determine how AMPK-mediated histone acetylation regulates human AML, by
generating patient-derived xenograft models of AML. Taken together, this proposal will establish the link between
metabolism and epigenetics, more specifically the links between acetyl-CoA metabolism, AMPK, and histone
acetylation. We hypothesize that these interactions are essential to recruit transcriptional regulators to key
leukemogenic genes. In the next funding cycle, we anticipate to unveil new insights that will inform us on how
metabolic regulators could be targeted to sensitize AML to epigenetic drugs, paving the way to novel
combinatorial therapies.

## Key facts

- **NIH application ID:** 10877011
- **Project number:** 5R01CA193235-10
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Daisuke Nakada
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $438,806
- **Award type:** 5
- **Project period:** 2015-04-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877011

## Citation

> US National Institutes of Health, RePORTER application 10877011, METABOLIC REGULATION IN LEUKEMIA-INITIATING CELLS (5R01CA193235-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10877011. Licensed CC0.

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