Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/218515
Title: Integrative single-cell expression and functional studies unravels a sensitization to cytarabine-based chemotherapy through HIF pathway inhibition in AML leukemia stem cells
Author: Abollo-Jiménez, Fernando
Velasco-Hernandez, Talia
Trincado, Juan L..
Vinyoles, Meritxell
Closa, Adrià
Martínez-Moreno, Alba
Gutiérrez-Agüera, Francisco
Molina, Òscar
Rodríguez Cortez, Virginia Carolina
Ximeno-Parpal, Pau
Fernández-Fuentes, Narcís
Petazzi, Paolo
Beneyto-Calabuig, Sergi
Velten, Lars
Romecín, Paola Alejandra
Casquero, Raquel
Diaz de la Guardia, Rafael
Lorden, Patricia
Bataller Torralba, Alex
Lapillonne, Helene
Stam, Ronald W.
Vives, Susana
Torrebadell Burriel, Montserrat
Fuster, José Luis
Bueno, Clara
Sarry, Jean-Emmanuel
Eyras, Eduardo
Heyn, Holger
Menéndez, Pablo
Keywords: Quimioteràpia del càncer
Leucèmia
Medul·la òssia
Resistència als medicaments
Cancer chemotherapy
Leukemia
Bone marrow
Drug resistance
Issue Date: 26-Feb-2024
Publisher: Wolters Kluwer
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.
Note: Reproducció del document publicat a: https://doi.org/10.1002/hem3.45
It is part of: Hemasphere, 2024, vol. 8, num.2
URI: https://hdl.handle.net/2445/218515
Related resource: https://doi.org/10.1002/hem3.45
ISSN: 2572-9241
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)

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