Acute myeloid leukemia (AML) is a multifactorial blood cancer driven not only by genetic mutations but also by complex interactions between leukemic cells and their surrounding microenvironment. This paper constructs a comprehensive molecular systems architecture that integrates signaling pathways across AML blasts, bone marrow stromal cells, endothelial cells, immune cells, osteoblasts, and adipocytes. Using a CytoSolve®-enabled systematic review process, the authors organize hundreds of peer-reviewed studies into a multi-layered interactome that captures intra- and inter-cellular communication driving AML progression. The resulting architecture demonstrates how signaling axes such as CXCR4/CXCL12, TGF-β, VEGF, IL-6, PD-1/PD-L1, and metabolic reprogramming collectively promote leukemic survival, angiogenesis, immune suppression, and drug resistance. By shifting focus from isolated mutations to system-wide signaling dynamics, the study provides a rational framework for identifying single and combination therapeutic strategies that target AML’s dependence on its microenvironment. This systems-level view offers new pathways for precision oncology and rational drug development in AML.
