Acute graft-versus-host disease (aGvHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT), occurring to some degree in over 50% of patients and being a direct cause of death in about 20% of patients. This complication occurs even despite a better understanding of donor selection and GvHD prophylaxis regimens. aGvHD is a complex event in which multiple contributing factors are involved. We performed RNA transcriptome analysis of 1408 genes in bone marrow samples obtained before and after transplantation using machine learning to predict the risk of aGvHD and post-transplant survival for a cohort of patients undergoing HSCT. Differential gene expression identified several signaling pathways in the bone marrow microenvironment that may be major regulators of the complex biology of GvHD, and identified targets of intervention to ameliorate the risk of aGvHD and improve patient survival.