Evaluation of the role of the melatonergic system in the development of Acute Myeloid Leukemias

Abstract

Changes in the Bone Marrow (BM) microenvironment, via inadequate production of immune/hormonal mediators and dysregulated interactions between hematopoietic and mesenchymal cells, are associated with the development of Acute Myeloid Leukemia (AML). Medullary TNF induces the local production of melatonin, which regulates self-renewal and retention of hematopoietic stem cells in BM. Although the melatonin produced by some types of solid tumors is a favorable prognostic factor, previous analyses of public databases indicate that high melatonin levels are associated with lower survival of patients with AML. In this project, we will evaluate the role of the melatonergic system in AML, combining bioinformatics analyzes and studies in human AML and mesenchymal cell lines. Previous data allow us to hypothesize that the inflammatory environment increases melatonin production in leukemic cells via NF-ºB activation. We will also test whether melatonin increases the expression of Cx43 connexin, favoring the communication between tumor and mesenchymal cells via gap junctions and tunneling nanotubes. These processes favor the transfer of mitochondria to tumor cells, increasing their survival and resistance to chemotherapy. Finally, since Cx43 increases ATP output from cells, melatonin would increase the activity of P2X7 purinergic receptors, reinforcing the inflammatory aspect of the tumor microenvironment. (AU)