Cancer Letters 479 (2020) 61–70 Contents lists available at Science Direct

 Cancer Letters 479 (2020) 61–70 Contents lists available at ScienceDirect Cancer Letters journal homepage: www.elsevier.com/locate/canlet Original Articles Monensin, a novel potent MYB inhibitor, suppresses proliferation of acute T myeloid leukemia and adenoid cystic carcinoma cells a a b a a Maria V. Yusenko , Amke Trentmann ,Mattias K. Andersson ,Luca Abdel Ghani , Anke Jakobs , c c d b Mari-Francis Arteaga Paz , Jan-Henrik Mikesch , Jens Peter von Kries , Göran Stenman , a,∗ Karl-Heinz Klempnauer a Institute for Biochemistry, Westfälische-Wilhelms-Universität, D-48149, Münster, Germany b Sahlgrenska Cancer Center, Department of Pathology, University of Gothenburg, Gothenburg, Sweden c Department of Medicine A, Hematology and Oncology, University Hospital, Westfälische-Wilhelms-Universität, Münster, Germany d Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany ARTICLE INFO ABSTRACT Keywords: The master transcriptional regulator MYB is a key oncogenic driver in several human neoplasms, particularly in MYB acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). MYB is therefore an attractive target for AML drug development in MYB-activated malignancies. Here, we employed a MYB-reporter cell line and identified ACC thepolyetherionophoresmonensin,salinomycin,andnigericinasnovelinhibitorsofMYBactivity.Asaproofof Monensin principle, we show thatmonensin affects theexpression of asignificantnumber of MYB-regulated genes inAML Salinomycin cells and causes down-regulation of MYB expression, loss of cell viability, and induction of differentiation and Polyether ionophore apoptosis. Furthermore, monensin significantly inhibits proliferation of primary murine AML 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 mo- lecular scaffolds for development of novel MYB inhibitors. 1. Introduction were found in a significant fr###http://www.glpbio.com/simage/GA11233-L-NAME-hydrochloride-1.png####action of T-ALL cases in children, thereby contributing to the development of leukemia by TAL1 or LMO2 over- MYB is an oncogenic transcription factor that is emerging as an expression[9,10].Furthermore,AMLcellswereshowntobe “addicted” important drug target for malignancies driven by MYB (MYB proto- to high levels of MYB GW311616, making them more vulnerable to inhibition of oncogene, transcription factor) activation, such as acute myeloid leu- MYB than normal hematopoietic progenitor cells [11,12]. This has led kemia (AML) and adenoid cystic carcinoma (ACC) [1–3]. MYB is totheconceptofatherapeuticwindowinwhichtheleukemiccellsmay broadlyexpressedinimmaturecellsofthehematopoieticsystemwhere be pharmacologically targeted with a MYB inhibitor without affecting it plays key roles in controlling the transcription of genes involved in the normal hematopoietic progenitors 3xFLAG PEPTIDE stability. lineage determination, cell proliferation, and differentiation [4]. Al- MYB rearrangements have also been strongly implicated as onco- though retrovirally transduced versions of the MYB gene have been genic drivers in non-hematopoietic malignancies, most prominently in known for many years to induce myelomonocytic leukemia in chickens adenoid cystic carcinoma (ACC) [13] but also in diffuse low-grade pe- [5,6], the role of MYB in the development of human leukemia has only diatric glioma [14]. 

 

ACC is an aggressive cancer that preferentially become apparent in recent years. Rearrangements leading to increased occurs in the head and neck but also in other sites such as the breast, expression of an unaltered MYB gene were initially identified in T-cell lung, and skin. ACC has a poor long-term prognosis and there is no acute lymphoblastic leukemia (T-ALL) [7,8]. More recently, mutations curative treatment available for patients with recurrent or metastatic that create de novo binding sites for MYB upstream of the TAL1 (T-cell disease [15]. The genomic hallmark of ACC is chromosomal translo- acute leukemia protein 1) and LMO2 (LIM only domain 2) oncogenes cationsthatgeneratefusionsbetweentheMYBandNFIB(nuclearfactor ∗ Corresponding author KX2-391. E-mail address: klempna@uni-muenster.dge (K.-H. Klempnauer). https://doi.org/10.1016/j.canlet.2020.01.039 Received 24 October 2019; Received in revised form 24 January 2020; Accepted 29 January 2020 0304-3835/ © 2020 Published by Elsevier B.V.

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