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

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.

• Authors: Sergi Beneyto-Calabuig, Anne Kathrin Merbach, Jonas-Alexander Kniffka, Magdalena Antes, Chelsea Szu-Tu, Christian Rohde, Alexander Waclawiczek, Patrick Stelmach, Sarah Gräßle, Philip Pervan, Maike Janssen, Jonathan J M Landry, Vladimir Benes, Anna Jauch, Michaela Brough, Marcus Bauer, Birgit Besenbeck, Julia Felden, Sebastian Bäumer, Michael Hundemer, Tim Sauer, Caroline Pabst, Claudia Wickenhauser, Linus Angenendt, Christoph Schliemann, Andreas Trumpp, Simon Haas, Michael Scherer, Simon Raffel, Carsten Müller-Tidow, Lars Velten
• Journal: Cell stem cell (Cell Stem Cell) Vol. 30 Issue 5 Pg. 706-721.e8 (05 04 2023) ISSN: 1875-9777 [Electronic] United States
• PMID: 37098346 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Topics

• Humans
• Multiomics
• Leukemia, Myeloid, Acute (genetics)
• Cell Differentiation
• Neoplastic Stem Cells (metabolism)