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Cited by 96Acute Myeloid Leukemia ResearchSingle-cell and spatial transcriptomicsCancer Genomics and Diagnostics

Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia

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Beneyto-Calabuig, Sergi, Merbach, Anne Kathrin, Kniffka, Jonas-Alexander, Antes, Magdalena, Szu-Tu, Chelsea, Rohde, Christian, Waclawiczek, Alexander, Stelmach, Patrick +23 more·2023·Cell Stem Cell
DOI 10.1016/j.stem.2023.04.001

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Abstract

Inter-patient variability and the similarity of healthy and leukemic stem cells (LSCs) have impeded the characterization of LSCs in acute myeloid leukemia (AML) and their differentiation landscape. Here, we introduce CloneTracer, a novel method that adds clonal resolution to single-cell RNA-seq datasets. Applied to samples from 19 AML patients, CloneTracer revealed routes of leukemic differentiation. Although residual healthy and preleukemic cells dominated the dormant stem cell compartment, active LSCs resembled their healthy counterpart and retained erythroid capacity. By contrast, downstream myeloid progenitors constituted a highly aberrant, disease-defining compartment: their gene expression and differentiation state affected both the chemotherapy response and leukemia's ability to differentiate into transcriptomically normal monocytes. Finally, we demonstrated the potential of CloneTracer to identify surface markers misregulated specifically in leukemic cells. Taken together, CloneTracer reveals a differentiation landscape that mimics its healthy counterpart and may determine biology and therapy response in AML.

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  • Such epigenetic alterations can potentially explain the shift toward activation observed for many TF combinations in K562 cells and the co-expression of stem and progenitor genes frequently observed in leukemia.

    “Such epigenetic alterations can potentially explain the shift toward activation observed for many TF combinations in K562 cells and the co-expression of stem and progenitor genes11 frequently observed in leukemia.”

    From Design principles of cell-state-specific enhancers in hematopoiesis (2025) · cites this paper as [11]

    In “LSCs retain erythroid capacity” (page unavailable), the paper reports that leukemic C6 cells expressed HSC-associated genes in some patients and genes associated with early erythromyeloid priming. This supports the cited point that stem- and progenitor-associated expression can coexist in AML cells, but does not establish that such co-expression is frequent across leukemia generally. The citation is attached to that co-expression point, not to the proposed epigenetic explanation or the K562 result. (LLM, conf=0.82)

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Cited by

Sorted by citations

Authors
Beneyto-Calabuig, S., Merbach, A. K., Kniffka, J.-A., Antes, M., Szu-Tu, C., Rohde, C., Waclawiczek, A., Stelmach, P., Gräßle, S., Pervan, P., Janssen, M., Landry, J. J. M., Benes, V., Jauch, A., Brough, M., Bauer, M., Besenbeck, B., Felden, J., Bäumer, S., Hundemer, M., Sauer, T., Pabst, C., Wickenhauser, C., Angenendt, L., Schliemann, C., Trumpp, A., Haas, S., Scherer, M., Raffel, S., Müller-Tidow, C., & Velten, L.
Affiliations
  • Heidelberg University (DE)
  • University Hospital Heidelberg (DE)
  • German Cancer Research Center (DE)
  • Max Delbrück Center (DE)
  • Barcelona Institute of Science and Technology (ES)
  • European Molecular Biology Laboratory (DE)
  • University Hospital in Halle (DE)
  • University Hospital Münster (DE)
  • ETH Zurich (CH)
  • Universitat Pompeu Fabra (ES)
Corresponding author
Velten, Lars
ORCID
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2023-05
Volume
30
Issue
5
Pages
706-721.e8
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
DOI
10.1016/j.stem.2023.04.001
OpenAlex
W4366824744
Cited by
96
References
11
Citations by year
2026: 22 · 2025: 33 · 2024: 31 · 2023: 8 · 2022: 2
FWCI
19.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell stem cell (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (acceptedVersion, cc-by)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion, cc-by)
  • Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
  • ETH Zürich Research Collection
Funders
  • Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg (INST 35/1503-1 FUGG)
  • Ministerio de Ciencia e Innovación
  • José Carreras Leukämie-Stiftung
  • Deutsches Krebsforschungszentrum
  • Deutsche Forschungsgemeinschaft (INST 35/1314-1 FUGG, MU1328/18-1, MU1328/21-1, MU1328/23-1)
  • Bundesministerium für Bildung und Forschung (031L0212A)
  • Centre de Regulació Genòmica
  • Agencia Estatal de Investigación (PID2019-108082GA-I00, PRE2020-093229)
  • Universitat Pompeu Fabra
  • University of the East
  • Emerson Collective (643577)
  • Department of Medicine, Georgetown University
  • Deutsche Krebshilfe (70113908)
  • European Molecular Biology Laboratory
  • European Regional Development Fund
  • Ministerio de Ciencia, Innovación y Universidades
  • Bundesministerium fur Bildung und Forschung Dienststelle Berlin
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
acute myeloid leukemia, leukemia stem cells, single-cell RNA sequencing, cell differentiation, myeloid progenitor cells, erythroid differentiation, chemotherapy response, monocyte differentiation, preleukemic cells, cell surface markers, interpatient variability
MeSH terms
Multiomics, Cell Differentiation, Humans, Neoplastic Stem Cells, Leukemia, Myeloid, Acute

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