Abollo-Jiménez, FernandoVelasco-Hernandez, TaliaTrincado, Juan L..Vinyoles, MeritxellClosa, AdriàMartínez-Moreno, AlbaGutiérrez-Agüera, FranciscoMolina, ÒscarRodríguez Cortez, Virginia CarolinaXimeno-Parpal, PauFernández-Fuentes, NarcísPetazzi, PaoloBeneyto Calabuig, SergiVelten, LarsRomecín, Paola AlejandraCasquero, RaquelDiaz de la Guardia, RafaelLorden, PatriciaBataller Torralba, AlexLapillonne, HeleneStam, Ronald W.Vives, SusanaTorrebadell Burriel, MontserratFuster, José LuisBueno, ClaraSarry, Jean-EmmanuelEyras, EduardoHeyn, HolgerMenéndez, Pablo2025-02-042025-02-042024-02-262572-9241https://hdl.handle.net/2445/218515Relapse 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.16 p.application/pdfengcc-by (c) Velasco-Hernandez, Talia et al., 2024http://creativecommons.org/licenses/by/4.0/Quimioteràpia del càncerLeucèmiaMedul·la òssiaResistència als medicamentsCancer chemotherapyLeukemiaBone marrowDrug resistanceinfo:eu-repo/semantics/article7459062025-02-04info:eu-repo/semantics/openAccess38435427