Integrative single-cell expression and functional studies unravels a sensitization to cytarabine-based chemotherapy through HIF pathway inhibition in AML leukemia stem cells

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  • dc.contributor.author Velasco Hernandez, Talia
  • dc.contributor.author Beneyto Calabuig, Sergi
  • dc.contributor.author Velten, Lars
  • dc.contributor.author Lorden, Patricia
  • dc.contributor.author Eyras Jiménez, Eduardo
  • dc.contributor.author Heyn, Holger
  • dc.contributor.author Menéndez, Pablo
  • dc.date.accessioned 2024-07-26T06:41:05Z
  • dc.date.available 2024-07-26T06:41:05Z
  • dc.date.issued 2024
  • dc.description.abstract Relapse remains a major challenge in the clinical management of acute myeloid leukemia (AML) and is driven by rare therapy-resistant leukemia stem cells (LSCs) that reside in specific bone marrow niches. Hypoxia signaling maintains cells in a quiescent and metabolically relaxed state, desensitizing them to chemotherapy. This suggests the hypothesis that hypoxia contributes to the chemoresistance of AML-LSCs and may represent a therapeutic target to sensitize AML-LSCs to chemotherapy. Here, we identify HIFhigh and HIFlow specific AML subgroups (inv(16)/t(8;21) and MLLr, respectively) and provide a comprehensive single-cell expression atlas of 119,000 AML cells and AML-LSCs in paired diagnostic-relapse samples from these molecular subgroups. The HIF/hypoxia pathway signature is attenuated in AML-LSCs compared with more differentiated AML cells but is more expressed than in healthy hematopoietic cells. Importantly, chemical inhibition of HIF cooperates with standard-of-care chemotherapy to impair AML growth and to substantially eliminate AML-LSCs in vitro and in vivo. These findings support the HIF pathway in the stem cell-driven drug resistance of AML and unravel avenues for combinatorial targeted and chemotherapy-based approaches to specifically eliminate AML-LSCs.
  • dc.description.sponsorship This research was also supported by the Spanish Ministry of Economy and Competitiveness (SAF2016-80481R, PID2019-108160RB-I00/AEI/10.13039/50110011033), “la Caixa” Foundation (LCF/PR/HR19/52160011), the Leo Messi Foundation, “Heroes hasta la médula” initiative, Departament de Recerca i Universitats de la Generalitat de Catalunya (2021 SGR 00887) and ISCIII-RICORS within the Next Generation EU program (plan de recuperación, transformación y resiliencia) to PM and the Health Institute Carlos III (ISCIII/FEDER, PI20/00 822) to Clara Bueno.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Velasco-Hernandez T, Trincado JL, Vinyoles M, Closa A, Martínez-Moreno A, Gutiérrez-Agüera F, et al. Integrative single-cell expression and functional studies unravels a sensitization to cytarabine-based chemotherapy through HIF pathway inhibition in AML leukemia stem cells. Hemasphere. 2024 Feb 26;8(2):e45. DOI: 10.1002/hem3.45
  • dc.identifier.doi http://dx.doi.org/10.1002/hem3.45
  • dc.identifier.issn 2572-9241
  • dc.identifier.uri http://hdl.handle.net/10230/60848
  • dc.language.iso eng
  • dc.publisher Wiley
  • dc.relation.ispartof Hemasphere. 2024 Feb 26;8(2):e45
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-80481R
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-108160RB-I00
  • dc.rights © 2024 The Authors. HemaSphere published by John Wiley & Sons Ltd. on behalf of European Hematology Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.subject.other Leucèmia mieloide aguda
  • dc.title Integrative single-cell expression and functional studies unravels a sensitization to cytarabine-based chemotherapy through HIF pathway inhibition in AML leukemia stem cells
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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