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

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 data...

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Autores: Beneyto Calabuig, Sergi, Szu-Tu, Chelsea, Velten, Lars
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Recursos:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/57259
Acesso em linha:http://hdl.handle.net/10230/57259
http://dx.doi.org/10.1016/j.stem.2023.04.001
Access Level:acceso abierto
Palavra-chave:AML
CSC
HSC
LSC
Acute myeloid leukemia
Cancer stem cells
Cellular differentiation
Computational biology
Computational method
Hematopoietic stem cells
Leukemic stem cells
Single-cell RNA-seq
Single-cell genomics
Single-cell transcriptomics
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spelling Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemiaBeneyto Calabuig, SergiSzu-Tu, ChelseaVelten, LarsAMLCSCHSCLSCAcute myeloid leukemiaCancer stem cellsCellular differentiationComputational biologyComputational methodHematopoietic stem cellsLeukemic stem cellsSingle-cell RNA-seqSingle-cell genomicsSingle-cell transcriptomicsInter-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.This work was financially supported by the German Bundesministerium für Bildung und Forschung (BMBF) through the Juniorverbund in der Systemmedizin “LeukoSyStem” (FKZ 01ZX1911D to L.V. and S.R.) as well as the Verbundprojekt SMART-CARE (031L0212A to C.M.-T.), the Emerson foundation grant 643577 (to L.V.), grant PID2019-108082GA-I00 and PRE2020-093229 by the Spanish Ministry of Science, Innovation and Universities (MCIU/AEI/FEDER, UE), the German Research Foundation (DFG; projects MU1328/18-1 and MU1328/21-1 and MU1328/23-1 to C.M.-T.), and the German Cancer Aid (DKH; project 70113908 to C.M.-T.). L.V. acknowledges support of the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme/Generalitat de Catalunya. C.M.-T., A.K.M., and J.-A.K. gratefully acknowledge the data storage service SDS@hd supported by the Ministry of Science, Research and the Arts Baden-Württemberg (MWK) and the German Research Foundation (DFG) through grant INST 35/1314-1 FUGG and INST 35/1503-1 FUGG. J.-A.K. acknowledges support of the Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie e.V. (DGHO) and Deutsche José Carreras Leukämie-Stiftung e.V. through the José Carreras-DGHO-Promotionsstipendium.Elsevier202320232023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/57259http://dx.doi.org/10.1016/j.stem.2023.04.001reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésCell Stem Cell. 2023 May 4;30(5):706-21.e8info:eu-repo/grantAgreement/ES/2PE/PID2019-108082GA-I00info:eu-repo/grantAgreement/ES/2PE/PRE2020-093229© 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/572592026-06-12T07:21:37Z
dc.title.none.fl_str_mv Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia
title Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia
spellingShingle Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia
Beneyto Calabuig, Sergi
AML
CSC
HSC
LSC
Acute myeloid leukemia
Cancer stem cells
Cellular differentiation
Computational biology
Computational method
Hematopoietic stem cells
Leukemic stem cells
Single-cell RNA-seq
Single-cell genomics
Single-cell transcriptomics
title_short Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia
title_full Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia
title_fullStr Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia
title_full_unstemmed Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia
title_sort Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia
dc.creator.none.fl_str_mv Beneyto Calabuig, Sergi
Szu-Tu, Chelsea
Velten, Lars
author Beneyto Calabuig, Sergi
author_facet Beneyto Calabuig, Sergi
Szu-Tu, Chelsea
Velten, Lars
author_role author
author2 Szu-Tu, Chelsea
Velten, Lars
author2_role author
author
dc.subject.none.fl_str_mv AML
CSC
HSC
LSC
Acute myeloid leukemia
Cancer stem cells
Cellular differentiation
Computational biology
Computational method
Hematopoietic stem cells
Leukemic stem cells
Single-cell RNA-seq
Single-cell genomics
Single-cell transcriptomics
topic AML
CSC
HSC
LSC
Acute myeloid leukemia
Cancer stem cells
Cellular differentiation
Computational biology
Computational method
Hematopoietic stem cells
Leukemic stem cells
Single-cell RNA-seq
Single-cell genomics
Single-cell transcriptomics
description 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.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/57259
http://dx.doi.org/10.1016/j.stem.2023.04.001
url http://hdl.handle.net/10230/57259
http://dx.doi.org/10.1016/j.stem.2023.04.001
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Cell Stem Cell. 2023 May 4;30(5):706-21.e8
info:eu-repo/grantAgreement/ES/2PE/PID2019-108082GA-I00
info:eu-repo/grantAgreement/ES/2PE/PRE2020-093229
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,198674

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