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Monensin, a novel potent MYB inhibitor, suppresses proliferation of acute myeloid leukemia and adenoid cystic carcinoma cells

Journal article
Authors M. V. Yusenko
A. Trentmann
Mattias K Andersson
L. A. Ghani
A. Jakobs
M. F. A. Paz
J. H. Mikesch
J. P. von Kries
Göran Stenman
K. H. Klempnauer
Published in Cancer Letters
Volume 479
Pages 61-70
ISSN 0304-3835
Publication year 2020
Published at Sahlgrenska Cancer Center
Institute of Biomedicine
Pages 61-70
Language en
Links dx.doi.org/10.1016/j.canlet.2020.01...
Keywords MYB, AML, ACC, Monensin, Salinomycin, Polyether ionophore, transcription factor myb, c-myb, stem-cells, v-myb, rearrangements, activation, oncogene, gene, differentiation, transformation, Oncology
Subject categories Cancer and Oncology

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.

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