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Genomic Classification and Prognosis in Acute Myeloid Leukemia
Open accessAbstract
BACKGROUND: Recent studies have provided a detailed census of genes that are mutated in acute myeloid leukemia (AML). Our next challenge is to understand how this genetic diversity defines the pathophysiology of AML and informs clinical practice. METHODS: We enrolled a total of 1540 patients in three prospective trials of intensive therapy. Combining driver mutations in 111 cancer genes with cytogenetic and clinical data, we defined AML genomic subgroups and their relevance to clinical outcomes. RESULTS: We identified 5234 driver mutations across 76 genes or genomic regions, with 2 or more drivers identified in 86% of the patients. Patterns of co-mutation compartmentalized the cohort into 11 classes, each with distinct diagnostic features and clinical outcomes. In addition to currently defined AML subgroups, three heterogeneous genomic categories emerged: AML with mutations in genes encoding chromatin, RNA-splicing regulators, or both (in 18% of patients); AML with TP53 mutations, chromosomal aneuploidies, or both (in 13%); and, provisionally, AML with IDH2(R172) mutations (in 1%). Patients with chromatin-spliceosome and TP53-aneuploidy AML had poor outcomes, with the various class-defining mutations contributing independently and additively to the outcome. In addition to class-defining lesions, other co-occurring driver mutations also had a substantial effect on overall survival. The prognostic effects of individual mutations were often significantly altered by the presence or absence of other driver mutations. Such gene-gene interactions were especially pronounced for NPM1-mutated AML, in which patterns of co-mutation identified groups with a favorable or adverse prognosis. These predictions require validation in prospective clinical trials. CONCLUSIONS: The driver landscape in AML reveals distinct molecular subgroups that reflect discrete paths in the evolution of AML, informing disease classification and prognostic stratification. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT00146120.).
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“Splicing factor mutations are common in AMl and other blood malignancies and are often mutually exclusive (Haferlach et al. 2014;Papaemmanuil et al. 2016), indicating that cancers harboring such mutations may rely on an intact splicing machinery for survival (lee et al. 2018).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Papaemmanuil et al. 2016
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“Leukemia is frequently driven by mutations in epigenetic modifiers or signaling master regulators58 that lead to gross alterations of the epigenetic landscape59 and an epigenetic environment widely permissive of activation.”
From Design principles of cell-state-specific enhancers in hematopoiesis (2025) · cites this paper as [58]
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“Particularly in acute myeloid leukemia (AML), a prominent component of the disease is recurrent mutations in spliceosome machinery and genome-wide aberrant splicing events (14)(15)(16)(17).”
From Discovery of a Novel CIP2A Variant (NOCIVA) with Clinical Relevance in Predicting TKI Resistance in Myeloid Leukemias (2021) · cites this paper as [16]
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“We identified 391 out of the 622 curated COSMIC cancer-related and AML-related genes located inside the altered TADs in at least one sample, and more than 100 are recurrent across multiple samples (Extended Data Fig. 3b)4,24,25.”
From Subtype-specific 3D genome alteration in acute myeloid leukaemia (2022) · cites this paper as [4]
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Metadata
- Authors
- Papaemmanuil, E., Gerstung, M., Bullinger, L., Gaidzik, V. I., Paschka, P., Roberts, N. D., Potter, N. E., Heuser, M., Thol, F., Bolli, N., Gundem, G., Van Loo, P., Martincorena, I., Ganly, P., Mudie, L., McLaren, S., O’Meara, S., Raine, K., Jones, D. R., Teague, J. W., Butler, A. P., Greaves, M. F., Ganser, A., Döhner, K., Schlenk, R. F., Döhner, H., & Campbell, P. J.
- Affiliations
- European Bioinformatics Institute (GB)
- Wellcome Sanger Institute (GB)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2016-06-09
- Volume
- 374
- Issue
- 23
- Pages
- 2209-2221
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4979995
- OpenAlex
- W2419140434
- Cited by
- 4,350
- References
- 40
- Citations by year
- 2026: 345 · 2025: 403 · 2024: 468 · 2023: 460 · 2022: 551 · 2021: 583 · 2020: 481 · 2019: 415 · 2018: 286 · 2017: 282 · 2016: 63
- FWCI
- 331.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Funders
- Wellcome Trust (103858/Z/14/Z, 105104, 077012/Z/05/Z, 077012, 103858, 105104/Z/14/Z, WT088340MA)
- Francis Crick Institute (10202)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- acute myeloid leukemia, driver mutations, genomic subgroups, prognostic stratification, TP53 mutation, aneuploidy, NPM1 mutation, IDH2 mutation, gene-gene interaction, co-mutation patterns, overall survival, intensive treatment
- MeSH terms
- DNA Methyltransferase 3A, Nucleophosmin, Adult, DNA (Cytosine-5-)-Methyltransferases, DNA Mutational Analysis, Epistasis, Genetic, Genotype, Humans, Middle Aged, Mutation, Nuclear Proteins, Prognosis, Prospective Studies, RNA Splicing, Leukemia, Myeloid, Acute, Proportional Hazards Models, Survival Analysis, Intracellular Signaling Peptides and Proteins, Gene Fusion
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