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Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations

2021; Springer Nature; Volume: 35; Issue: 10 Linguagem: Inglês

10.1038/s41375-021-01318-x

1476-5551

Giorgia Simonetti, Carlo Mengucci, Antonella Padella, Eugenio Fonzi, Gianfranco Picone, Claudio Delpino, Jacopo Nanni, Rossella De Tommaso, Eugenia Franchini, Cristina Papayannidis, Giovanni Marconi, Martina Pazzaglia, Margherita Perricone, Emanuela Scarpi, Maria Chiara Fontana, Samantha Bruno, Michela Tebaldi, Anna Ferrari, Maria Teresa Bochicchio, Andrea Ghelli Luserna di Rorà, Martina Ghetti, Roberta Napolitano, Annalisa Astolfi, Carmen Baldazzi, Viviana Guadagnuolo, Emanuela Ottaviani, Ilaria Iacobucci, Michèle Cavo, Gastone Castellani, Torsten Haferlach, Daniel Remondini, Francesco Capozzi, Giovanni Martinelli,

Histone Deacetylase Inhibitors Research

Although targeting of cell metabolism is a promising therapeutic strategy in acute myeloid leukemia (AML), metabolic dependencies are largely unexplored. We aimed to classify AML patients based on their metabolic landscape and map connections between metabolic and genomic profiles. Combined serum and urine metabolomics improved AML characterization compared with individual biofluid analysis. At intracellular level, AML displayed dysregulated amino acid, nucleotide, lipid, and bioenergetic metabolism. The integration of intracellular and biofluid metabolomics provided a map of alterations in the metabolism of polyamine, purine, keton bodies and polyunsaturated fatty acids and tricarboxylic acid cycle. The intracellular metabolome distinguished three AML clusters, correlating with distinct genomic profiles: NPM1-mutated(mut), chromatin/spliceosome-mut and TP53-mut/aneuploid AML that were confirmed by biofluid analysis. Interestingly, integrated genomic-metabolic profiles defined two subgroups of NPM1-mut AML. One was enriched for mutations in cohesin/DNA damage-related genes (NPM1/cohesin-mut AML) and showed increased serum choline + trimethylamine-N-oxide and leucine, higher mutation load, transcriptomic signatures of reduced inflammatory status and better ex-vivo response to EGFR and MET inhibition. The transcriptional differences of enzyme-encoding genes between NPM1/cohesin-mut and NPM1-mut allowed in silico modeling of intracellular metabolic perturbations. This approach predicted alterations in NAD and purine metabolism in NPM1/cohesin-mut AML that suggest potential vulnerabilities, worthy of being therapeutically explored.