Evaluation of intracellular nucleotide pools in peripheral blood and bone marrow mononuclear cells and their association with frontline intensive chemotherapy response rates in AML patients

Abstract

Aim: Resistance to frontline intensive chemotherapy remains a major clinical challenge in acute myeloid leukemia (AML). Currently, refractory AML is mostly observed in certain genotypes. In in vitro experiments, primary resistance in AML has been associated with nucleotide metabolism. However, the relationship between in vivo nucleotide metabolism, genotype, and the occurrence of complete remission (CR) remains largely unexplored. We aimed to investigate the potential association between in vivo nucleotide pools at AML diagnosis, genotype, and the efficacy of frontline intensive chemotherapy.

Methods: In this prospective pilot study, we quantified the intracellular nucleotide pools in peripheral blood (PBMC) and bone marrow mononuclear cells (BMMC) from 70 AML patients at diagnosis. Nucleotide levels were compared depending on genotype data and the occurrence of CR after the frontline intensive chemotherapy.

Results: No relationship was observed between nucleotide levels and genotype. Specific alterations of certain nucleotide levels in cells from patients who did not achieve CR were identified: elevated guanosine triphosphate (GTP) levels in BMMC and uridine monophosphate (UMP) levels in PBMC, as well as reduced adenosine monophosphate (AMP) levels and energy ratios [AMP/adenosine triphosphate (ATP), AMP + adenosine diphosphate (ADP)/ATP] in PBMC. These results may suggest impaired activity of enzymes such as UMP/cytidine monophosphate (CMP) kinase and reduced AMP-activated protein kinase (AMPK) activation in patients who did not achieve CR.

Conclusion: Our study provides the first in vivo data linking specific alterations in intracellular nucleotide levels to the efficacy of the frontline intensive chemotherapy in AML. These findings offer a novel perspective on the role of nucleotide metabolism in the primary resistance in frontline intensive chemotherapy.

Keywords

Nucleotides / acute myeloid leukemia / peripheral blood mononuclear cells / bone marrow mononuclear cells / frontline intensive chemotherapy / chemoresistance

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