Abstract 3957: Receptor Activator of NF-κB (RANK) confers resistance to chemotherapy in AML and associates with dismal disease course

Abstract Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Untreated, AML leads to death within months after first symptoms. Combinatorial chemotherapy, mostly using a pyrimidine analog together with an anthracycline, made this previously incurable disease medicable, and response to remission-inducing chemotherapy strongly correlates with patient outcome. Despite advances in treatment over the recent years, AML still has a poor prognosis with an average 5-year survival rate of 30%. A better understanding of the molecular mechanisms predicting and affecting treatment efficacy is key to improve disease control and outcome. Here we studied the expression, prognostic relevance and functional role of the tumor necrosis factor receptor (TNFR) family member Receptor Activator of Nuclear Factor (NF)-κB (RANK) in AML. We conducted an experimental ex vivo study using leukemic cells of 54 AML patients. Substantial surface expression of RANK was detected on the primary AML cells in 35% of the analyzed patients. We further found that RANK signaling induced the release of the cytokines IL-6, IL-8, TNF and IL-10 acting as growth and survival factors for the leukemic cells and mediated resistance of AML cells to treatment with doxorubicin and cytarabine, the most commonly used cytostatic compounds in AML treatment. In line, prevalence of RANK expression on leukemic cells correlated with dismal disease course of patients as revealed by reduced overall survival. Together, our results show that RANK plays a yet unrecognized role in AML pathophysiology and resistance to treatment. Moreover, the association of RANK expression with adverse disease course identifies RANK as potential “functional” prognostic marker and putative target for therapeutic intervention to improve treatment response of AML patients. Citation Format: Kim L. Clar, Lisa M. Weber, Bastian J. Schmied, Jonas S. Heitmann, Maddalena Marconato, Claudia Tandler, Pascal Schneider, Helmut R. Salih. Receptor Activator of NF-κB (RANK) confers resistance to chemotherapy in AML and associates with dismal disease course [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3957.