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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.

Adrenomedullin Expression Characterizes Leukemia Stem Cells and Associates With an Inflammatory Signature in Acute Myeloid Leukemia