Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations
| Autor: | Samantha Bruno, Andrea Ghelli Luserna di Rorà, Anna Maria Ferrari, Giovanni Marconi, Rossella De Tommaso, Carlo Mengucci, Maria Teresa Bochicchio, Cristina Papayannidis, Margherita Perricone, Antonella Padella, Francesco Capozzi, Claudio Delpino, Torsten Haferlach, Jacopo Nanni, Emanuela Ottaviani, Emanuela Scarpi, Martina Pazzaglia, Gastone Castellani, Eugenia Franchini, Giovanni Martinelli, Gianfranco Picone, Martina Ghetti, Annalisa Astolfi, Maria Chiara Fontana, Ilaria Iacobucci, Giorgia Simonetti, Michele Cavo, Roberta Napolitano, Viviana Guadagnuolo, Michela Tebaldi, Eugenio Fonzi, Daniel Remondini, Carmen Baldazzi |
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| Přispěvatelé: | Simonetti, Giorgia, Mengucci, Carlo, Padella, Antonella, Fonzi, Eugenio, Picone, Gianfranco, Delpino, Claudio, Nanni, Jacopo, De Tommaso, Rossella, Franchini, Eugenia, Papayannidis, Cristina, Marconi, Giovanni, Pazzaglia, Martina, Perricone, Margherita, Scarpi, Emanuela, Fontana, Maria Chiara, Bruno, Samantha, Tebaldi, Michela, Ferrari, Anna, Bochicchio, Maria Teresa, Ghelli Luserna Di Rorà, Andrea, Ghetti, Martina, Napolitano, Roberta, Astolfi, Annalisa, Baldazzi, Carmen, Guadagnuolo, Viviana, Ottaviani, Emanuela, Iacobucci, Ilaria, Cavo, Michele, Castellani, Gastone, Haferlach, Torsten, Remondini, Daniel, Capozzi, Francesco, Martinelli, Giovanni |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Cancer Research Chromosomal Proteins Non-Histone Metabolic alteration Cell Cycle Proteins medicine.disease_cause 0302 clinical medicine hemic and lymphatic diseases Cancer genomics Genomic subgroup Purine metabolism Aged 80 and over Mutation Myeloid leukemia Nuclear Proteins Hematology Genomics Middle Aged Prognosis Cancer metabolism Chromatin 3. Good health Metabolic cluster Leukemia Myeloid Acute Oncology 030220 oncology & carcinogenesis Molecular classification Female Nucleophosmin Adult NPM1 congenital hereditary and neonatal diseases and abnormalities Adolescent DNA damage Metabolomic Biology Article Acute myeloid leukaemia 03 medical and health sciences Young Adult Metabolomics medicine Metabolome Humans Aged 030104 developmental biology Cancer research DNA Damage |
| Zdroj: | Leukemia |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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