BET Inhibition Suppresses S100A8 and S100A9 Expression in Acute Myeloid Leukemia Cells and Synergises with Daunorubicin in Causing Cell Death.

Helen J S Stewart,Timothy J T Chevassut,Freya Luiling Feilding,Sabah Chaudry,Asante Crichlow

doi:10.1155/2018/5742954

Helen J S Stewart, Timothy J T Chevassut + Show 3 more

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https://doi.org/10.1155/2018/5742954

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Journal: Bone Marrow Research	Publication Date: May 31, 2018
Citations: 13	License type: CC BY 4.0

Affiliation: Brighton and Sussex Medical School

Abstract

S100A8 and S100A9 are both members of the S100 family and have been shown to play roles in myeloid differentiation, autophagy, apoptosis, and chemotherapy resistance. In this study we demonstrate that the BET-bromodomain inhibitor JQ1 causes rapid suppression of S100A8 and S100A9 mRNA and protein in a reversible manner. In addition, we show that JQ1 synergises with daunorubicin in causing AML cell death. Daunorubicin alone causes a dose- and time-dependent increase in S100A8 and S100A9 protein levels in AML cell lines which is overcome by cotreatment with JQ1. This suggests that JQ1 synergises with daunorubicin in causing apoptosis via suppression of S100A8 and S100A9 levels.

Highlights

Acute myeloid leukemia is the most common leukemia in adults accounting for around 80% of cases [1]
Microarray experiments conducted on leukemia cell lines treated with the bromodomain inhibitor JQ1 showed that JQ1 causes a significant downregulation of S100A8 and S100A9 transcripts in OCI-AML3 cells (Figure 1)
We initially conducted experiments to confirm the levels of S100A8 and S100A9 mRNA in these cell lines and to determine S100A8 and S100A9 expression in bone marrow mononuclear cells (BMMCs) and peripheral blood mononuclear cells (PBMCs)

Summary

Introduction

Acute myeloid leukemia is the most common leukemia in adults accounting for around 80% of cases [1]. It is a clonal disorder of the myeloid lineage of white blood cells characterised by the arrest of differentiation of immature ‘blast’ cells in the bone marrow. Diagnosis and posttreatment monitoring of AML are generally accomplished using a combination of karyotype analysis and reverse transcriptase polymerase chain reaction (RT-PCR) or fluorescent in situ hybridization (FISH) for specific abnormalities. Around half of AML patients have a normal karyotype and intermediate prognosis. With limited exceptions little improvement in outcome for AML patients has been achieved with only around 35% of younger fit patients cured of their disease. Additional cellular targets need to be identified in order to develop new chemotherapeutic treatment strategies

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