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Cited by 140Acute Myeloid Leukemia ResearchEpigenetics and DNA MethylationCancer Genomics and Diagnostics

Single-cell multi-omics of human clonal hematopoiesis reveals that DNMT3A R882 mutations perturb early progenitor states through selective hypomethylation

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Nam, Anna S., Dusaj, Neville, Izzo, Franco, Murali, Rekha, Myers, Robert M., Mouhieddine, Tarek H., Sotelo, Jesus, Benbarche, Salima +9 more·2022·Nature Genetics
DOI 10.1038/s41588-022-01179-9PMC PMC10068894
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Abstract

Somatic mutations in cancer genes have been detected in clonal expansions across healthy human tissue, including in clonal hematopoiesis. However, because mutated and wild-type cells are admixed, we have limited ability to link genotypes with phenotypes. To overcome this limitation, we leveraged multi-modality single-cell sequencing, capturing genotype, transcriptomes and methylomes in progenitors from individuals with DNMT3A R882 mutated clonal hematopoiesis. DNMT3A mutations result in myeloid over lymphoid bias, and an expansion of immature myeloid progenitors primed toward megakaryocytic-erythroid fate, with dysregulated expression of lineage and leukemia stem cell markers. Mutated DNMT3A leads to preferential hypomethylation of polycomb repressive complex 2 targets and a specific CpG flanking motif. Notably, the hypomethylation motif is enriched in binding motifs of key hematopoietic transcription factors, serving as a potential mechanistic link between DNMT3A mutations and aberrant transcriptional phenotypes. Thus, single-cell multi-omics paves the road to defining the downstream consequences of mutations that drive clonal mosaicism.

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  • CD9 and VWF are closely associated with MkP differentiation.

    “In the MkPs, we identified a downregulation of CD9 and VWF , closely associated with MkP differentiation 46-49 , upon IFNa treatment ( Supplementary Fig. 4b ) which is consistent with the decrease in the proportion of MkP observed after IFNa treatment.”

    From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [46]

    The Results section on the DNMT3A-mutated bone marrow sample says CD9 expression has been linked with megakaryocytic differentiation priming and examines it along that differentiation trajectory. The passages found do not establish the same association for VWF; they also do not address IFNa treatment, which the citing sentence presents as its own finding. No page number was provided for these passages. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In MkPs, CD9 and VWF were downregulated upon IFNa treatment.

    “In the MkPs, we identified a downregulation of CD9 and VWF , closely associated with MkP differentiation 46-49 , upon IFNa treatment ( Supplementary Fig. 4b ) which is consistent with the decrease in the proportion of MkP observed after IFNa treatment.”

    From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [46]

    The Results section (page unavailable) links CD9 expression to megakaryocytic priming, supporting the differentiation-related point to which the citation is attached. It does not establish the same link for VWF. The IFNa-associated downregulation is presented as the citing authors’ own finding, not as a result attributed to this source. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Nam, A. S., Dusaj, N., Izzo, F., Murali, R., Myers, R. M., Mouhieddine, T. H., Sotelo, J., Benbarche, S., Waarts, M., Gaiti, F., Tahri, S., Levine, R., Abdel-Wahab, O., Godley, L. A., Chaligne, R., Ghobrial, I., & Landau, D. A.
Affiliations
  • New York Genome Center (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • Dana-Farber Cancer Institute (US)
  • University of Chicago (US)
Corresponding author
  • Ghobrial, Irene
  • Landau, Dan A.
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2022-09-22
Volume
54
Issue
10
Pages
1514-1526
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-022-01179-9
PMC
PMC10068894
OpenAlex
W4296683167
Cited by
140
References
37
Citations by year
2026: 26 · 2025: 27 · 2024: 36 · 2023: 39 · 2022: 11 · 2021: 1
FWCI
20.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Bristol-Myers Squibb
  • GlaxoSmithKline
  • Sanofi
  • National Institutes of Health (1dp2ca239065-01, DP5OD029619)
  • Weill Cornell Medical College (T32GM007739)
  • Loxo Oncology
  • National Heart, Lung, and Blood Institute (R01HL145283, F30HL156496)
  • National Human Genome Research Institute (RM1HG011014)
  • National Cancer Institute (DP2-CA239065, P30CA008748)
  • National Institute of General Medical Sciences (T32GM007739)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
clonal hematopoiesis, myeloid progenitor cells, polycomb repressive complex 2, CpG motifs, transcription factor binding motifs, clonal mosaicism, genotype-phenotype linkage, single-cell multi-omics
MeSH terms
Clonal Hematopoiesis, DNA Methyltransferase 3A, DNA (Cytosine-5-)-Methyltransferases, Hematopoiesis, Humans, Mutation, DNA Modification Methylases, Polycomb Repressive Complex 2

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