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Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations
- Source :
- Leukemia
- Publication Year :
- 2021
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Leukemia
- Accession number :
- edsair.doi.dedup.....16d1620846c56e989a1a90f1eceb54ba