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

Adolescent Adult Aged Aged, 80 and over Cell Cycle Proteins / genetics Chromatin / genetics Chromosomal Proteins, Non-Histone / genetics DNA Damage / genetics Female Genomics / methods Humans Leukemia, Myeloid, Acute / genetics Male Middle Aged Mutation / genetics Nuclear Proteins / genetics Nucleophosmin Prognosis Young Adult Cohesins

Journal

Leukemia

ISSN: 1476-5551

Titre abrégé: Leukemia

Pays: England

ID NLM: 8704895

Informations de publication

Date de publication:
10 2021

Historique:

received: 11 03 2021

accepted: 02 06 2021

revised: 21 05 2021

pubmed: 2 7 2021

medline: 18 11 2021

entrez: 1 7 2021

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41375-021-01318-x PMID: 34193978 PMC: PMC8478658

pubmed: 34193978

doi: 10.1038/s41375-021-01318-x

pii: 10.1038/s41375-021-01318-x

pmc: PMC8478658

doi:

Substances chimiques

Cell Cycle Proteins 0

Chromatin 0

Chromosomal Proteins, Non-Histone 0

NPM1 protein, human 0

Nuclear Proteins 0

Nucleophosmin 117896-08-9

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

2813-2826

Subventions

Organisme : European Hematology Association (EHA)

ID : EHA Research Fellowship

Organisme : Ministero della Salute (Ministry of Health, Italy)

ID : GR-2018-12365278

Informations de copyright

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