# Defining and targeting the metabolic landscape in Acute Myeloid Leukemia

> **NIH NIH K99** · RESEARCH INST OF FOX CHASE CAN CTR · 2020 · $108,686

## Abstract

PROJECT SUMMARY/ABSTRACT
Acute Myeloid Leukemia (AML) is an aggressive blood cancer that arises from the aberrant expansion of mutated
myeloid-skewed hematopoietic stem and progenitor cells (HSPCs). Given that the current 5-year survival rate
for AML patients is below 25%, novel, more effective therapies are desperately needed. Targeting cellular energy
production has recently become as a promising point of therapeutic intervention in many cancers including AML.
This study aims to uncover the metabolic alterations that support AML pathogenesis and to exploit this
information to identify new potential therapeutic targets in AML.
We have found that compared to healthy HSPCs, AML cells are more sensitive to perturbations in mitochondria,
which are the epicenters of cellular energy. In search of molecular pathways that selectively support metabolism
in AML cells but not healthy HSPCs, we recently discovered that the kinase PKCε supports AML survival and
progression by preserving redox balance. To gain a deeper understanding of how PKCε does this, we carried
out a proteomics analysis and found that PKCε regulates the expression of several mitochondrial and metabolic
proteins, including Electron Transport Chain (ETC) complex subunits, transporters, and metabolic enzymes.
Follow-up metabolomics analyses in AML cells confirmed that several metabolic pathways, in particular
glycolysis and gluconeogenesis, are severely disrupted by PKCε inhibition. A comparative analysis of proteomic
and metabolomic data revealed that PKCε regulates multiple enzymatic pinch points within glycolysis. To identify
which of the PKCε-regulated glycolytic enzymes may be supporting AML, we performed a retrospective analysis
of AML patient gene expression data and observed that increased expression of Enolase (ENO1) is associated
with significantly worse AML patient outcomes. Additionally, we found that inhibition of ENO1 activity either
genetically or chemically significantly reduces the growth and survival of AML but, of critical importance, not
healthy HSPCs. The aims of this proposal are to leverage these observations by:
1) Defining the role of PKCε in AML cellular metabolism;
2) Assessing the therapeutic potential of targeting PKCε-regulated metabolic enzymes, such as ENO1, in AML.
The results of this proposal will uncover new metabolic dependences in AML as well as molecular targets that
can serve as a basis for developing novel AML therapies.
Based on these preliminary data and proposed studies, the central mission of my career plan is to decipher how
metabolism influence leukemogenesis and to identify new molecular targets that can be exploited for therapeutic
intervention.

## Key facts

- **NIH application ID:** 9969478
- **Project number:** 5K99CA241370-02
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** Daniela Di Marcantonio
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $108,686
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969478

## Citation

> US National Institutes of Health, RePORTER application 9969478, Defining and targeting the metabolic landscape in Acute Myeloid Leukemia (5K99CA241370-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9969478. Licensed CC0.

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