Stem Cell Metabolic Dysfunction in Myeloid Leukaemia and its Therapeutic Targeting

Acute myeloid leukaemia (AML) is the most common form of acute leukaemia occurring in adults. Its incidence increases with age and the prognosis for the older patient remains bleak. Overcoming these problems will require a better understanding of AML. Interestingly, cancer and normal cells differ in their metabolism that is their way of obtaining energy. Alterations in different steps of metabolic pathways link to cancer development and resistance to therapies. Furthermore, surrounding or distal normal cells can sense metabolic disturbances in cancer cells through sensing of metabolic intermediates, usually present inside the cell but released outside under particular conditions such as metabolic stress. These pathways have received little attention in the context of leukaemia. In spite of significant delays due to external reasons that the group has experienced throughout the years, we have been able to make significant contributions to the objectives of the project. The metabolic intermediate succinate and its receptor (Sucnr1) have been scarcely explored in the context of hematopoiesis under health or disease to date. Here, we show that low SUCNR1 represents a marker for reduced survival in AML patients. Treatments with succinate promoted disease progression in mouse models of pre-leukaemic myelopoiesis and AML, as well as in AML xenografts. In vivo global deletion of Sucnr1 induced expansion of haematopoietic stem and progenitor cells (HSPC) and haematopoiesis. Independent deletion of Sucnr1 from the haematopoietic system resulted in expansion of multipotent progenitors and differentiated cells, while deletion of Sucnr1 from Nestin+ stromal cells promoted expansion of the stem cell compartment, in a CXCL12-independent manner. Our data reveal that Sucnr1 preserves transcriptional programs characteristic of HSPC via control of S100a8/S100a9. Together, Sucnr1 signaling is a key regulatory pathway in the haematopoietic system that involves both the haematopoietic and stromal compartments of the bone marrow, and its dysregulation contributes to haematopoietic malignancies via control of S100a8/S100a9. This project provides insights into the basic processes that regulate blood stem cell function/dysfunction and knowledge of markers for patient prognosis. The therapeutic potential of these findings should be further explored in future research.

The research developed in this project has uncovered Sucnr1 signaling as a key regulatory pathway in the haematopoietic system that involves both the haematopoietic and stromal compartments of the bone marrow, and its dysregulation contributes to haematopoietic malignancies via control of S100a8/S100a9. Future research should further focus on the characterization of the therapeutic value of using Sucnr1 and/or S100a8/S100a9 as targets in the treatment of haematopoietic malingnancies.

Acute myeloid leukaemia (AML) is the most common form of acute leukaemia occurring in adults. Its incidence increases with age and the prognosis for the older patient remains bleak. Overcoming these problems will require a better understanding of AML. Growing data links altered cellular metabolism to tumourigenesis and resistance to therapies in several types of cancer. Interestingly, altered cell metabolism can be sensed among neighbouring or distal cells through succinate signalling, but this pathway has received little attention in the context of leukaemia. The primary aim of this project is to investigate the potential role of succinate signalling dysfunction in AML pathogenesis and its importance to human AML. A transgenic mouse model expressing the human N-RASG12D mutation in an inducible manner will be used, which confers HSC with a survival/proliferative advantage but it is not sufficient to recapitulate AML. Signalling through the Krebs cycle intermediate product succinate will be manipulated in vivo through drugs and additional genetic engineering aiming to induce leukaemic transformation in N-RASG12D mice, and in turn, allowing the potential value of succinate signalling to be tested in novel therapeutic strategies. Further, we will discriminate the potential contribution of the bone marrow niche in this process. Changes observed in mouse models will be validated in human patient samples. Thus, the present research will give insights into the basic processes that regulate HSC function/dysfunction and will allow the application of this knowledge to provide a novel platform for more efficient therapies against AML.