The alamandine/MrgD axis: A novel paracrine pathway within bone marrow RAS-driven leukemogenesis

Introduction The local hematopoietic bone marrow (BM) renin–angiotensin system (RAS) is a complex network of tissue-specific signaling pathways operating through autocrine, paracrine, and intracrine mechanisms that govern stem cell fate, lineage commitment, and marrow microenvironmental integrity. Neoplastic dysregulation of the local BM RAS drives leukemogenesis through a shift toward the proliferative angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/angiotensin type 1 receptor (AT1R) axis. The discovery of alamandine and its receptor, Mas-related G protein-coupled receptor D (MrgD), has expanded the non-classical RAS paradigm by introducing a distinct protective signaling branch. Method The alamandine–MrgD axis within the local BM RAS and its role in leukemic transformation was examined and synthesized by searching PubMed/MEDLINE using keywords including alamandine, MrgD receptor, bone marrow renin–angiotensin system, and leukemogenesis. Conclusions The alamandine–MrgD axis exerts anti-proliferative, anti-inflammatory, and antioxidant effects that counterbalance oncogenic ACE/Ang II/AT1R signaling in the hematopoietic marrow microenvironment. This axis functions as an endogenous counter-regulatory component of the BM RAS, modulating cellular proliferation, inflammatory signaling, oxidative stress, and microenvironmental homeostasis during leukemic transformation, positioning it as a critical regulator of physiological hematopoiesis. The biological expression and activity of the alamandine–MrgD axis may serve as both a prognostic biomarker and a therapeutic target in leukemia management.