# The EAAT1 aspartate/glutamate transporter is dispensable for acute myeloid leukemia cell growth and response to therapy

## TL;DR

This study shows that blocking the EAAT1 transporter does not stop the growth of acute myeloid leukemia cells or improve their response to treatment.

## Contribution

The study reveals that EAAT1 is not essential for AML cell growth or therapy response despite its role in aspartate transport.

## Key findings

- EAAT1 is expressed in AML cell lines and patient samples, especially in M4 and M5 subtypes.
- AML cells can maintain growth without EAAT1 or aspartate, suggesting alternative aspartate sources.
- EAAT1 inhibition in mice did not reduce AML growth or improve chemotherapy sensitivity.

## Abstract

Acute myeloid leukemia (AML) is an aggressive malignancy of hematopoietic stem and progenitor cells characterized by profound metabolic dysregulation. Pyrimidine biosynthesis has emerged as a critical metabolic dependency in AML, but clinical translation has been hampered by unacceptable toxicity of current pyrimidine synthesis inhibitors. Since aspartate is an essential nutrient for pyrimidine biosynthesis, we investigated the role of aspartate import via the excitatory amino acid transporter 1 (EAAT1) in AML. We found that EAAT1 is broadly expressed across AML cell lines and patient samples, with enrichment in M4 and M5 subtypes and increasing levels following chemotherapy treatment. Pharmacological inhibition of EAAT1 impaired AML cell viability in vitro, but metabolomic profiling and nutrient rescue experiments showed that these effects were independent of intracellular aspartate levels. Moreover, AML cells cultured in aspartate-free medium maintained proliferation and did not become more sensitive to chemotherapy. EAAT1 inhibition in mice increased bone marrow plasma aspartate levels, confirming inhibition of cellular aspartate uptake, but did not affect growth or chemosensitivity of MLL-AF9-expressing AML cells in vivo. These findings suggest that AML cells possess several complementary mechanisms to support their aspartate requirements and that EAAT1 inhibition does not impair AML growth or response to chemotherapy.