Carregant...
Fitxers
Tipus de document
ArticleVersió
Versió publicadaData de publicació
Llicència de publicació
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/218515
Integrative single-cell expression and functional studies unravels a sensitization to cytarabine-based chemotherapy through HIF pathway inhibition in AML leukemia stem cells
Títol de la revista
Director/Tutor
ISSN de la revista
Títol del volum
Recurs relacionat
Resum
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.
Matèries (anglès)
Citació
Citació
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. 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. Vol. 8, núm. 2. [consulta: 24 de gener de 2026]. ISSN: 2572-9241. [Disponible a: https://hdl.handle.net/2445/218515]