RESUMEN
SUMMARY: Although inflammation has long been recognized as a hallmark of many cancers, including acute myeloid leukemia (AML), how it affects individual cells of the tumor microenvironment and their interaction with normal and neoplastic cells is incompletely understood. A comprehensive single-cell transcriptomic analysis of human bone marrow from patients with AML and healthy individuals identified skewing of stem cell and stromal cell populations in AML toward proinflammatory states associated with reduced risk of relapse, paralleling previous findings in mouse models and suggesting that inflamed bone marrow mesenchymal stromal cells might be a double-edged sword in AML by hampering normal hematopoiesis (while AML cells appear comparatively more resilient) but also rendering AML cells more susceptible to chemotherapy or immune attack. See related article by Chen et al., p. 394 (7) .
Asunto(s)
Leucemia Mieloide Aguda , Células Madre Mesenquimatosas , Animales , Ratones , Humanos , Leucemia Mieloide Aguda/genética , Modelos Animales de Enfermedad , Estado de Salud , Inflamación , Microambiente Tumoral/genéticaRESUMEN
Eradicating leukemia requires a deep understanding of the interaction between leukemic cells and their protective microenvironment. The CXCL12/CXCR4 axis has been postulated as a critical pathway dictating leukemia stem cell (LSC) chemoresistance in AML due to its role in controlling cellular egress from the marrow. Nevertheless, the cellular source of CXCL12 in the acute myeloid leukemia (AML) microenvironment and the mechanism by which CXCL12 exerts its protective role in vivo remain unresolved. Here, we show that CXCL12 produced by Prx1+ mesenchymal cells but not by mature osteolineage cells provide the necessary cues for the maintenance of LSCs in the marrow of an MLL::AF9-induced AML model. Prx1+ cells promote survival of LSCs by modulating energy metabolism and the REDOX balance in LSCs. Deletion of Cxcl12 leads to the accumulation of reactive oxygen species and DNA damage in LSCs, impairing their ability to perpetuate leukemia in transplantation experiments, a defect that can be attenuated by antioxidant therapy. Importantly, our data suggest that this phenomenon appears to be conserved in human patients. Hence, we have identified Prx1+ mesenchymal cells as an integral part of the complex niche-AML metabolic intertwining, pointing towards CXCL12/CXCR4 as a target to eradicate parenchymal LSCs in AML.
Asunto(s)
Médula Ósea , Leucemia Mieloide Aguda , Médula Ósea/metabolismo , Metabolismo Energético , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Células Madre Neoplásicas/metabolismo , Oxidación-Reducción , Microambiente TumoralRESUMEN
How blood stem cells balance fate decisions between quiescence maintenance and differentiation during recovery from cancer treatment remains poorly understood. A recent study by Umemoto et al (2022) uncovers an unexpected linkage between metabolic and epigenetic regulation of haematopoiesis, suggesting new targets in haematopoietic regeneration, with possible implications in leukaemogenesis and therapy resistance.
