Receptor Activator of NF-κB (RANK) Confers Resistance to Chemotherapy in AML and Associates with Dismal Disease Course.

Kim Clar,Bastian Schmied,Maddalena Marconato,Helmut Salih,Claudia Tandler,Jonas Heitmann,Pascal Schneider,Lisa Weber

doi:10.3390/cancers13236122

Abstract

Simple SummaryAcute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Despite the emergence of new therapeutic agents in recent years, curation remains challenging, and new and better treatment options are needed. In the present study, we investigated the expression, prognostic significance, and functional role of the Receptor Activator of Nuclear Factor-κB (RANK) in AML. We found that RANK is expressed on leukemic cells in a substantial proportion of AML patients and is associated with a dismal disease course. We further demonstrated that signaling via RANK induces release of factors that favor AML cell survival and confers resistance to chemotherapeutics in AML treatment. Together, our findings identify RANK as novel prognostic marker and putative candidate for therapeutic intervention in AML to enhance response to treatment. Although treatment options of acute myeloid leukemia (AML) have improved over the recent years, prognosis remains poor. Better understanding of the molecular mechanisms influencing and predicting treatment efficacy may 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 primary AML cells in 35% of the analyzed patients. We further found that RANK signaling induced the release of cytokines 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, RANK expression correlated with a dismal disease course as revealed by reduced overall survival. Together, our results show that RANK plays a yet unrecognized role in AML pathophysiology and resistance to treatment, and identify RANK as “functional” prognostic marker in AML. Therapeutic modulation of RANK holds promise to improve treatment response in AML patients.

Highlights

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and characterized by a clonal expansion of myeloid precursor cells with a reduced capacity to differentiate [1,2]
We analyzed various AML cell lines to determine whether RANK is expressed on these malignant hematopoietic cells
RANK expression was confirmed by determination of mRNA levels using quantitative PCR (Figure 1B)

Summary

Introduction

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and characterized by a clonal expansion of myeloid precursor cells with a reduced capacity to differentiate [1,2]. AML leads to death within months after first symptoms [3]. Curation remains challenging and complications, such as refractory disease and relapse caused by treatmentresistant cells, lead to a poor prognosis with an average 5-year survival rate of 30% [6,7]. Despite the development and approval of several new therapeutic agents in recent years, AML-related deaths are expected to almost double worldwide by 2040 [8]. This underlines the high medical need of patients and the necessity to develop better treatment options based on the discovery of novel druggable targets [9,10]

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Conclusion