The AML cellular state space unveils NPM1 immune evasion subtypes with distinct clinical outcomes
Acute myeloid leukemia is a genetically and cellularly heterogeneous disease. We characterize 120 AMLs using genomic and transcriptomic analyses, including single-cell RNA sequencing. Our results reveal an extensive cellular heterogeneity that distorts the bulk transcriptomic profiles. Selective examination of the transcriptional signatures of >90,000 immature AML cells identifies four main clusters, thereby extending current genomic classification of AML. Notably, NPM1-mutated AML can be stratified into two clinically relevant classes, with NPM1<sup>class I</sup> associated with downregulation of MHC class II and excellent survival following hematopoietic stem cell transplantation. NPM1<sup>class II</sup> is instead associated with resistance to allogeneic T cells in an ex vivo co-culture assay, and importantly, dismal survival following hematopoietic stem cell transplantation. These findings provide insights into the cellular state space of AML, define diagnostic entities, and highlight potential therapeutic intervention points.
Authors
- Helena Ågerstam (ORCID: https://orcid.org/0009-0002-8216-3876)
- Rasmus Henningsson
- Henrik Lilljebjörn (ORCID: https://orcid.org/0000-0001-8703-1173)
- Petr Staněk (ORCID: https://orcid.org/0009-0003-6856-8575)
- Vendela Rissler
- Carl Sandén (ORCID: https://orcid.org/0000-0002-8931-9565)
- Thoas Fioretos (ORCID: https://orcid.org/0000-0002-3235-6154)
- Pablo Peña‐Martínez (ORCID: https://orcid.org/0000-0002-0789-6431)
- Xiangfu Zhong (ORCID: https://orcid.org/0000-0002-1872-1186)
- Marianne Rissler
- Sofia von Palffy (ORCID: https://orcid.org/0000-0001-5640-4037)
- Noelia Puente‐Moncada (ORCID: https://orcid.org/0000-0002-5996-2349)
- Sören Lehmann (ORCID: https://orcid.org/0000-0001-8374-8978)
- Gunnar Juliusson (ORCID: https://orcid.org/0000-0002-9457-5272)
- Jonathan Desponds (ORCID: https://orcid.org/0000-0001-7112-3217)
- Niklas Landberg (ORCID: https://orcid.org/0000-0001-6752-6507)
- Hanna Thorsson (ORCID: https://orcid.org/0000-0001-5393-2942)
- Christina Orsmark‐Pietras (ORCID: https://orcid.org/0000-0002-6533-0305)
- Vladimir Lazarević (ORCID: https://orcid.org/0000-0002-1782-4423)
- Magnus Fontes
Institutions
- Lund University (SE)
- Science for Life Laboratory (SE)
- Symphogen (Denmark) (DK)
- Integrated Cardio Metabolic Centre (SE)
- Roche (France) (FR)
- Skåne University Hospital (SE)
- Lund Science (Sweden) (SE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-25
- DOI
- https://doi.org/10.1038/s41467-025-66546-6
- Citations
- 1
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 1.77
Funders
- Mats Paulssons Stiftelse
- Cancerfonden
- Lunds Universitet
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Science for Life Laboratory