ABSTRACT

Chemoresistance is the difference between remission and cure in cancer patients and is particularly evident in acute myeloid leukemia (AML) where complete remissions are common, but few are cured. Prior work by us and others shows that AML cells have distinctive metabolic dependencies compared with their normal counterparts. We hypothesized that residual chemoresistant cells must pass through extreme metabolic challenges. Capturing cells at the moment of maximal response showed a metabolite profile that was distinct from AML cells at pre-chemo growth or post-chemo relapse. Metabolite set enrichment analysis revealed hyperactivation of glutamine metabolism, with chemoresistant cells showing high levels of glutamine, glutamate and aspartate. Pharmacological or genetic inhibition of glutamine metabolism during the window of maximal response reduced the number of chemoresistant cells and lead to improved survival in mouse models of AML. Mechanistically, we found that chemoresistant AML cells have increased flux of glutamine-derived carbon to glutathione, while glutamine-derived nitrogen is used for nucleotide synthesis. Interestingly, while almost no glutamine entered the Krebs cycle in AML cells in vivo, we did find labeled aspartate, indicating that aspartate is not synthesized from glutamine by the AML cells themselves. Single cell RNA sequencing of the bone marrow niche revealed subsets of CXCL12-positive stromal cells expressing high levels of the aspartate transporter SLC1A3, which further increased in the presence of AML. In conclusion, we propose that induction of a timed metabolic collapse targeting leukemia cells both directly and indirectly can prevent chemoresistance development in AML and improve the rate of cure.