Monensin, a novel potent MYB inhibitor, suppresses proliferation of acute myeloid leukemia and adenoid cystic carcinoma cells. (1st June 2020)

• Record Type: Journal Article
• Authors: Yusenko, Maria V.; Trentmann, Amke; Andersson, Mattias K.; Ghani, Luca Abdel; Jakobs, Anke; Arteaga Paz, Mari-Francis; Mikesch, Jan-Henrik; Peter von Kries, Jens; Stenman, Göran; Klempnauer, Karl-Heinz
• Is Part Of: Cancer letters. Volume 479(2020)
• Page Start: 61
• Page End: 70
• Publication Date: 2020-06-01
• Subjects: MYB -- AML -- ACC -- Monensin -- Salinomycin -- Polyether ionophore; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.01.039
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The master transcriptional regulator MYB is a key oncogenic driver in several human neoplasms, particularly in acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). MYB is therefore an attractive target for drug development in MYB-activated malignancies. Here, we employed a MYB-reporter cell line and identified the polyether ionophores monensin, salinomycin, and nigericin as novel inhibitors of MYB activity. As a proof of principle, we show that monensin affects the expression of a significant number of MYB-regulated genes in AML cells and causes down-regulation of MYB expression, loss of cell viability, and induction of differentiation and apoptosis. Furthermore, monensin significantly inhibits proliferation of primary murine AML cells but not of normal hematopoietic progenitors, reflecting a high MYB-dependence of leukemic cells and underscoring the efficacy of monensin in MYB-activated malignancies. Importantly, monensin also suppressed the viability and non-adherent growth of adenoid cystic carcinoma (ACC) cells expressing MYB-NFIB fusion oncoproteins. Our data show that a single compound with significant MYB-inhibitory activity is effective against malignant cells from two distinct MYB-driven human neoplasms. Hence, monensin and related compounds are promising molecular scaffolds for development of novel MYB inhibitors. Highlights: Polyether ionophore monensin and related compounds inhibit MYB activity. Monensin induces differentiation and cell death in acute myeloid leukemia cells. Monensin inhibits viability of MYB-NFIB positive adenoid cystic carcinoma cells. Polyether ionophores as novel molecular scaffolds targeting MYB-driven malignancies.