Abstract
Adrenomedullin (ADM) is a hypotensive and vasodilator peptide belonging to the calcitonin gene-related peptide family. It is secreted in vitro by endothelial cells and vascular smooth muscle cells, and is significantly upregulated by a number of stimuli. Moreover, ADM participates in the regulation of hematopoietic compartment, solid tumors and leukemias, such as acute myeloid leukemia (AML). To better characterize ADM involvement in AML pathogenesis, we investigated its expression during human hematopoiesis and in leukemic subsets, based on a morphological, cytogenetic and molecular characterization and in T cells from AML patients. In hematopoietic stem/progenitor cells and T lymphocytes from healthy subjects, ADM transcript was barely detectable. It was expressed at low levels by megakaryocytes and erythroblasts, while higher levels were measured in neutrophils, monocytes and plasma cells. Moreover, cells populating the hematopoietic niche, including mesenchymal stem cells, showed to express ADM. ADM was overexpressed in AML cells versus normal CD34+ cells and in the subset of leukemia compared with hematopoietic stem cells. In parallel, we detected a significant variation of ADM expression among cytogenetic subgroups, measuring the highest levels in inv(16)/t(16;16) or complex karyotype AML. According to the mutational status of AML-related genes, the analysis showed a lower expression of ADM in FLT3-ITD, NPM1-mutated AML and FLT3-ITD/NPM1-mutated cases compared with wild-type ones. Moreover, ADM expression had a negative impact on overall survival within the favorable risk class, while showing a potential positive impact within the subgroup receiving a not-intensive treatment. The expression of 135 genes involved in leukemogenesis, regulation of cell proliferation, ferroptosis, protection from apoptosis, HIF-1α signaling, JAK-STAT pathway, immune and inflammatory responses was correlated with ADM levels in the bone marrow cells of at least two AML cohorts. Moreover, ADM was upregulated in CD4+ T and CD8+ T cells from AML patients compared with healthy controls and some ADM co-expressed genes participate in a signature of immune tolerance that characterizes CD4+ T cells from leukemic patients. Overall, our study shows that ADM expression in AML associates with a stem cell phenotype, inflammatory signatures and genes related to immunosuppression, all factors that contribute to therapy resistance and disease relapse.
Highlights
Adrenomedullin (ADM) is a 52-amino acid hormone belonging to the amylin/calcitonin gene-related peptide (CGRP) superfamily, that has been originally identified in the extracts of human pheochromocytoma [1]
It was barely detectable in megakaryocytes and erythroblasts, while increasing in dendritic cells (DC) and, especially, during neutrophilic differentiation and in monocytes (Figure 1A)
ADM expression is elevated in acute myeloid leukemia (AML) compared with acute lymphoblastic leukemia (ALL), in line with the observation that ADM expression is a main feature of the myeloid differentiation program
Summary
Adrenomedullin (ADM) is a 52-amino acid hormone belonging to the amylin/calcitonin gene-related peptide (CGRP) superfamily, that has been originally identified in the extracts of human pheochromocytoma [1]. It is produced by cleavage of an immature precursor that is synthesized by the ADM gene. ADM can exert local and systemic anti-inflammatory actions by regulating cytokine secretion [13] and immune system properties, with beneficial effects on inflammatory conditions as gastric ulcers [14] and bowel diseases [15]. Additional stimuli, as cell-to-cell interaction [16], growth factors, steroids, hormones, and physical factors, including oxidative stress and hypoxia, can induce ADM expression [3]
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