Facultad de Medicina - Tesis Doctorales y Tesinas - 2020-2029

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    Understanding niche-leukemia interactions: the bone marrow microenvironment regulates the metabolic and redox balance in acute myeloid leukemia stem cells
    (Universidad de Navarra, 2023-01-31) Ana Cristina; Rifon, J. J. (Jose J.); Saez, B. (Borja)
    Despite increasing evidence suggesting the importance of the hematopoietic stem cell (HSC) niche in the process of neoplastic transformation, the cellular identity of the niche and its contribution to the development of acute myeloid leukemia (AML) remains to be elucidated. Akin to their normal counterpart, leukemia stem cells (LSCs) reside in the bone marrow (BM) niche, from which receive cues contributing to their maintenance and localization. Cxcl12 is a key molecule implicated in HSC maintenance and is produced by multiple niche components including mesenchymal stromal cells (MSCs), osteolineage cells (OLCs) and endothelial cells (ECs). While CXCL12 levels in the BM of AML patients have not been formally evaluated, the overexpression of its canonical receptor, CXCR4, in leukemic blasts has been associated with poor prognosis. Moreover, pharmacological inhibition of the CXCL12-CXCR4 signaling axis contributes to sensitization of leukemic cells to chemotherapy by preventing the protective effect of the leukemia-stroma interaction. This evidence suggests that the CXCL12-CXCR4 axis is one of the critical factors in this interaction and its inhibition may represent a promising therapy in AML. Nevertheless, several critical aspects regarding the LSC-stroma interaction in the BM such as: 1) the cellular source of CXCL12 in the AML BM and 2) the cellular and molecular mechanism by which CXCL12 exert its protective role in AML in vivo, remain unresolved. Here, we show that Cxcl12 produced by Prx1+ MSCs, but not by mature osteolineage or ECs, provides the necessary cues for the maintenance of LSCs in MLL::9F9-driven AML. Prx1+ cells in the BM promotes survival of LSCs by modulating energy metabolism and the REDOX balance in AML. Specifically, Cxcl12 depletion results in a marked decrease in leukemic infiltration and the frequency of LSCs, as well as in a change in the composition of the leukemic clone, resulting in a significant prolonged survival. Furthermore, Prx1+ cells promote survival of LSCs by modulating energy metabolism and 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. Interestingly, our data suggest that this phenomenon appears to be conserved in human AML patients. In summary, 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.