Journal article

All-trans retinoic acid enhances, and a pan-RAR antagonist counteracts, the stem cell promoting activity of EVI1 in acute myeloid leukemia

Chi Huu Nguyen, Katharina Bauer, Hubert Hackl, Angela Schlerka, Elisabeth Koller, Anastasiya Hladik, Dagmar Stoiber, Johannes Zuber, Philipp B Staber, Andrea Hoelbl-Kovacic, Louise E Purton, Florian Grebien, Rotraud Wieser

CELL DEATH & DISEASE | NATURE PUBLISHING GROUP | Published : 2019

Abstract

Ecotropic virus integration site 1 (EVI1), whose overexpression characterizes a particularly aggressive subtype of acute myeloid leukemia (AML), enhanced anti-leukemic activities of all-trans retinoic acid (atRA) in cell lines and patient samples. However, the drivers of leukemia formation, therapy resistance, and relapse are leukemic stem cells (LSCs), whose properties were hardly reflected in these experimental setups. The present study was designed to address the effects of, and interactions between, EVI1 and retinoids in AML LSCs. We report that Evi1 reduced the maturation of leukemic cells and promoted the abundance, quiescence, and activity of LSCs in an MLL-AF9-driven mouse model of A..

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Grants

Awarded by Austrian Science Fund (FWF)


Funding Acknowledgements

This work was funded by the Austrian Science Fund (FWF), project no P28256-B28 to R.W. The FWF did not play any role in the design of the study, the writing of the manuscript, or its submission to "Cell Death & Disease". The authors gratefully acknowledge Christoph Bock and Michael Schuster from the Biomedical Sequencing Facility at the Center for Molecular Medicine, Vienna, Austria, for advice on and assistance with RNA-sequencing. Johannes Schmollerl and Petra Aigner, Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria, provided important practical advice regarding retroviral transduction of primary murine cells. Andreas Spittler, Core Facility Flow Cytometry, Medical University of Vienna, Vienna, Austria, performed cell sorts and gave invaluable advice for flow cytometry applications. Dr. Takuro Nakamura, Cancer Institute of JFCR, Tokyo, Japan, kindly provided pMSCV_Flag-Evi1_IRES_GFP. The authors wish to thank Dr. Georg Krupitza, Clinic of Pathology, and Dipl.-Ing. Alexander Grandits, Clinic of Medicine I, Medical University of Vienna, for critically reading the manuscript.