A new autophagy-related nomogram and mechanism in multiple myeloma

Abstract

Autophagy is an intracellular, self-degradative process that serves the cell energy sources balance and tissue homeostasis, and is critical in multiple myeloma (MM) pathogenesis, however, the prognostic role of autophagy-related genes (ARGs) in MM remains undefined. In the present study, ARGs were selected from Gene Expression Omnibus datasets containing 1038 samples from patients with MM. Furthermore, an autophagy risk score (ARS) model was developed using Cox regression analysis. Patients with MM could be stratified into high- and low-risk groups with distinct clinical outcomes by ARS. Moreover, we established a nomogram, including the independent prognostic factor ARS and the International Staging System, which can improve the prognostic performance of MM. Gene Ontology analysis revealed that most of pathways enriched for ARGs were related to autophagy and metabolism. Furthermore, the critical role of ARNT-mediated autophagy in MM cell proliferation and drug resistance were validated using in vivo and in vitro strategies. Mechanistically, ARNT expresses in various immune cells in the bone marrow microenvironment, forming a positive feedback loop with hypoxia. Moreover, ARNT exacerbates autophagy through activating AKT signaling pathway. In conclusion, this study constructed an ARG-based prognostic model to predict the prognosis of patients with MM and revealed that targeting specific autophagy genes may provide potential insights relevant to MM treatment.