2026-04-13T11:45:08Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/2185152025-11-20T13:50:29Zcom_2072_1057col_2072_478799col_2072_478917

Integrative single-cell expression and functional studies unravels a sensitization to cytarabine-based chemotherapy through HIF pathway inhibition in AML leukemia stem cells 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 Quimioteràpia del càncer Leucèmia Medul·la òssia Resistència als medicaments Cancer chemotherapy Leukemia Bone marrow Drug resistance 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. 2025-02-04T19:11:15Z 2025-02-04T19:11:15Z 2024-02-26 2025-02-04T19:11:15Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Reproducció del document publicat a: https://doi.org/10.1002/hem3.45 Hemasphere, 2024, vol. 8, num.2 https://doi.org/10.1002/hem3.45 cc-by (c) Velasco-Hernandez, Talia et al., 2024 http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Wolters Kluwer Articles publicats en revistes (Ciències Fisiològiques)