Transcriptomic effects of purine metabolism inhibition and nucleolus rRNA synthesis disruption on murine acute myeloid leukemia stem cell

Through targeted metabolomics analysis of bulk leukemia cells and leukemia stem cells (LSCs) derived from the MLL-AF9-driven acute myeloid leukemia (AML) model, in comparison with normal granulocyte-monocyte progenitor (GMP) cells and whole bone marrow (WBM) cells from normal mice, we identified enhanced purine metabolism in AML LSCs. Pharmacological targeting of the purine metabolism using mycophenolate mofetil (MMF) resulted in decreased levels of purine metabolites crucial for nucleolus rRNA synthesis. Importantly, inhibition of purine metabolism or disruption of the nucleolus rRNA synthesis, achieved by inhibiting pol I activity with CX-5461, triggered myeloid differentiation in the MLL-AF9-driven AML LSCs. These findings unveil a regulatory axis involving purine metabolism and nucleolar rRNA synthesis in maintaining AML LSC activity. Overall design: To investigate the function of purine metabolism and nucleolus rRNA synthesis in sustaining AML LSC activity, we isolated LSCs (defined by L-GMP immunophenotype) from MLL-AF9-driven AML mice and then treated them with MMF, CX-5461, Guanosine, or a combination of MMF and Guanosine. We performed gene expression profiling analysis using data obtained from these five distinct experimental groups. Our comparative analysis focused on the gene expression profiles of AML LSCs and treated LSCs.