Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia

The Cancer Genome Atlas Research Network

doi:10.1056/nejmoa1301689

Cited by 5,078Acute Myeloid Leukemia ResearchCancer Genomics and DiagnosticsChromatin Remodeling and Cancer

Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia

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The Cancer Genome Atlas Research Network·2013·New England Journal of Medicine

DOI 10.1056/nejmoa1301689PMC PMC3767041

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Abstract

BACKGROUND: Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. METHODS: We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. RESULTS: AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. CONCLUSIONS: We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.).

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Adults and patients with myeloid malignancies typically lack the ETV6-RUNX1 oncogene.
“in line with clinical observations of adults and patients with myeloid malignancies typically lacking this oncogene (43).”
From PU.1-Dependent Enhancer Inhibition Separates Tet2 -Deficient Hematopoiesis from Malignant Transformation (2022) · cites this paper as [43]
The Results > Gene Fusions section reports that 99 of 179 adult de novo AML samples had no detected gene fusion, so those samples lacked ETV6-RUNX1. The paper does not specifically discuss ETV6-RUNX1 or establish its prevalence across adults generally or across other myeloid malignancies. No page number is available in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Both TET2 and TET3 are highly expressed in this model and in human AML.
“both TET2 and TET3 are highly expressed in our model and in human AML27 (Supplementary Figure S2d).”
From Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia (2018) · cites this paper as [27]
Many of the most commonly seen mutations in CHIP are also recurrent drivers of AML, myelodysplastic syndrome (MDS), myeloproliferative neoplasms, and certain lymphomas.
“But many of the most commonly seen mutations in CHIP are also recurrent drivers of AML 64, myelodysplastic syndrome (MDS) 65–67, myeloproliferative neoplasms 68, and certain lymphomas 69,70.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [64]
Treatment of AML with targeted therapies is particularly promising due to the fact that AMLs have far fewer mutations than most other adult cancers, with an average of only 13 mutations.
“Treatment of AML with targeted therapies is particularly promising due to the fact that AMLs have far fewer mutations than most other adult cancers, with an average of only 13 mutations (Mardis et al, 2009; Cancer Genome Atlas Research Network, 2013).”
From Unlocking the potential of retinoic acid in anticancer therapy (2014) · cites this paper as Cancer Genome Atlas Research Network, 2013

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Authors: The Cancer Genome Atlas Research Network
Affiliations: Washington University in St. Louis (US)
Corresponding author: The Cancer Genome Atlas Research Network
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2013-05-30
Volume: 368
Issue: 22
Pages: 2059-2074
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejmoa1301689
PMC: PMC3767041
OpenAlex: W1255676896
Cited by: 5,078
References: 49
Citations by year: 2026: 195 · 2025: 277 · 2024: 335 · 2023: 415 · 2022: 465 · 2021: 509 · 2020: 485 · 2019: 466 · 2018: 361 · 2017: 424 · 2016: 382 · 2015: 343 · 2014: 304 · 2013: 108 · 2012: 2
FWCI: 271.87
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
eSpace (Curtin University) (submittedVersion)
Padua Research Archive (University of Padova) (submittedVersion)
Funders: National Institutes of Health
National Human Genome Research Institute (U54HG003067, U54HG003079, U54HG003273, R01HG005690)
National Cancer Institute (R01CA083962, U24CA143882, U24CA143843, U24CA143840, U24CA143858, U24CA144025, U24CA143866, U24CA143883, U24CA143845, R01CA162086, U24CA143867, U24CA143848, U24CA143799, U24CA143835, P01CA101937, P30CA016672, P30CA091842)
Topics: Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords: acute myeloid leukemia, de novo AML, adult AML, somatic mutations, epigenetics, DNA methylation, transcription factor fusion, NPM1, tumor suppressor, chromatin modifiers, driver mutations, risk stratification
MeSH terms: Nucleophosmin, Adult, Female, Humans, Male, Middle Aged, Mutation, Leukemia, Myeloid, Acute, Gene Expression, Genome, Human, Sequence Analysis, DNA, CpG Islands, DNA Methylation, MicroRNAs, Gene Fusion, Epigenomics

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Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia

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