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

Artikel i vetenskaplig tidskrift
Författare 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
Publicerad i Cancer Letters
Volym 479
Sidor 61-70
ISSN 0304-3835
Publiceringsår 2020
Publicerad vid Sahlgrenska Cancer Center
Institutionen för biomedicin
Sidor 61-70
Språk en
Länkar dx.doi.org/10.1016/j.canlet.2020.01...
Ämnesord MYB, AML, ACC, Monensin, Salinomycin, Polyether ionophore, transcription factor myb, c-myb, stem-cells, v-myb, rearrangements, activation, oncogene, gene, differentiation, transformation, Oncology
Ämneskategorier Cancer och onkologi

Sammanfattning

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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