Europe PMC

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy.

DNMT3A-R882 mutations intrinsically drive dysfunctional neutropoiesis from human haematopoietic stem cells

Show less

Author information

Affiliations

  • 1. Department of Haematology and , , ,
      Authors
    • Mantica G 1
    • Vedi A 1
    • Hayler D 1
    • Krzywon A 1
    • Dunn WG 1
    • Bastos HP 1
    • Sham K 1
    • Santoro A 1
    • Vassiliou GS 1
    • Fabre MA 1
    • Nangalia J 1, 4
    • Laurenti E 1
    (12 authors)
  • 2. Department of Molecular Cell Biology, , ,
      Authors
    • Tuval A 2
    • Biezuner T 2
    • Danin A 2
    • Chapal N 2
    • Moskovitz Y 2
    • Shlush L 2
    (6 authors)
  • 3. Haematopoietic Stem Cell Laboratory, , ,
      Authors
    • Huerga Encabo H 3
    • Bonnet D 3
    (2 authors)
  • 4. , , ,
      Authors
    • Mitchell E 4
    • Lee J 4
    • Williams N 4
    • Fiorillo E 4
    • Orru V 4
    • Marongiu M 4
    • Cucca F 4
    • Campbell P 4
    • Nangalia J 1, 4
    (9 authors)
  • 5. , , , ,
      Authors
    • Arruda A 5
    • Minden M 5
    (2 authors)
    • Show all (7)

Preprint from bioRxiv, 08 Oct 2025
https://doi.org/10.1101/2025.10.08.679225 PPR: PPR1096825 

Preprint

This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
Free full text in Europe PMC

This article is a preprint. It may not have been peer reviewed.
A preprint is a complete scientific manuscript that an author uploads on a public server for free viewing. Initially it is posted without peer review, but may acquire feedback or reviews as a preprint, and may eventually be published in a peer-reviewed journal. The posting of preprints on public servers allows almost immediate dissemination and scientific feedback early in the 'publication' process.

Abstract 

Clonal haematopoiesis (CH) arises from the expansion of hematopoietic stem cells (HSCs) carrying leukaemia-associated somatic mutations. CH is linked to pathological immune dysregulation and a greater risk of age-related inflammatory diseases. Yet, how CH mutations impact HSC differentiation into immune effector cells remains understudied. Here, we report a single-cell resolution functional and multi-omic investigation of HSC clonal and differentiation dynamics in individuals with DNMT3A-R882 CH. DNMT3A-R882 reshapes the clonal architecture of haematopoiesis towards an aged phylogenetic structure. Functionally, DNMT3A-R882 HSCs produce decreased monocytic output but more abundant and mature neutrophil progeny compared to WT HSCs in the same individual. Whereas DNMT3A-R882 myeloid progenitors display attenuated inflammatory transcriptional programmes, DNMT3A-R882 mature neutrophils acquire proinflammatory and immunomodulatory features typical of maladaptive immunity and CH co-morbidities. Our findings, validated in humanised mice, identify aberrant DNMT3A-R882 HSC-driven neutropoiesis as a key link between CH, immune dysregulation and risk of inflammatory disease.

Free full text 

loading

Full text links 

Read article at publisher's site: https://doi.org/10.1101/2025.10.08.679225

Citations & impact 

This article has not been cited yet.

loading

Data 

loading

Funding 

Funders who supported this work.

Blood Cancer UK (1)

  • Grant ID: 24008

    Loading publications

Wellcome Trust (1)

  • Grant ID: 107630/Z/15/Z

    Loading publications

  • Save
  • Open PDF
  • Claim to ORCID