Primary chemo-refractory disease and relapse are the most important causes of mortality in acute myeloid leukemia (AML) patients (Döhner et al., N. Engl. J. Med. 2015). Leukemia stem cells (LSCs) are likely responsible for disease relapse (Guzman et al., Blood 2007). Several genomic studies of newly-diagnosed and relapsed AML have revealed different patterns of clonal evolution, but little is known about metabolic dysregulations among these two groups. Metabolomics can identify endogenous cell metabolite biomarkers to be applied for monitoring disease progression, in order to develop new targeted therapies (D. Wang et al., Journal of Pharm and Biom Analysis 2019).
We aimed to identify relapse-specific metabolic alterations of CD34+ AML stem-progenitor cells.
We analyzed metabolites using mass spectrometry (Metabolon) of CD34+ bone-marrow stem progenitor cells of 22 newly-diagnosed and 13 relapsed AML patients. To better address the relevance of the results, we also compared our samples with CD34+ cells from umbilical cord blood (21 donors). Statistically-significant differences in metabolite concentrations between the groups were evaluated by Welch's t-test. KEGG and SMPDB annotation helped us in identifying the most relevant differences in terms of metabolic pathways.
Mass spectrometry analysis identified differences in the concentration of 16 metabolites between newly-diagnosed and relapsed AML. In particular, we discovered different intermediates of lipid metabolism, as decreased 1-(1-enyl-palmitoyl)-2-palmitoyl-GPC (p = 0,0049), or involved in Kreb's Cycle, like reduced fumarate (p = 0,0393) in relapsed AML. Conversely, we observed a higher concentration of UDP-N-acetylglucosamine/galactosamine (p = 0,0044), which is part of carbohydrate metabolism. Moreover, by comparing CD34+ cells from relapsed or newly-diagnosed AML with cord blood, we defined a set of metabolic features which may suggest metabolic adaptation of the post-chemotherapy AML clone. It is worth noting the decrease in uridine concentration (p = 0,03), a metabolite of pyrimidine metabolism. Pyrimidine pathway is of great interest thanks to the development of new drugs as dihydroorotate dehydrogenase (DHODH) inhibitor, that reduces leukemic cell burden, decreases levels of leukemia-initiating cells (Sykes DB et al., Cell 2016). Of note, relapsed cells show reduced orotidine levels compared with cells from newly-diagnosed patients. Finally, KEGG and SMPDB annotation revealed enrichment for changes in compounds involved in Ketone Body Metabolism, Citric Acid Cycle and Mitochondrial Electron Transport Chain.
Our data are in line with a metabolic reprogramming of AML cells at relapse, including a shift from pyruvate oxidation to fatty acid β-oxidation, with altered mitochondrial oxidative phosphorylation in leukemia stem progenitor cells. The results suggest potential metabolic vulnerabilities of relapsed patients which could be exploited for novel targeted therapeutic strategies. Supported by EHA research fellowship award.