Pluto Bioinformatics

GSE123255: All-trans retinoic acid cooperates with EVI1 to enhance key properties of acute myeloid leukemia stem cells

Bulk RNA sequencing

All-trans retinoic acid (atRA) is highly effective as a therapeutic agent in acute promyelocytic leukemia, but no definitive conclusions have yet been reached regarding its potential usefulness in other subtypes of acute myeloid leukemia (AML). Ecotropic virus integration site 1 (EVI1), an oncogene whose overexpression in AML is associated with a particularly aggressive course of disease, has been previously shown to enhance anti-leukemic activities of 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 not, or only to a very limited extent, reflected in these experimental setups. Using an MLL-AF9 driven mouse model of AML as well as human AML cell lines with stem cell properties, the present study therefore addressed the question whether EVI1 and atRA would also interact to affect the behaviour of LSCs. Indeed, EVI1 and atRA cooperated to enhance the abundance, quiescence, and activity of LSCs/LSC enriched cells, while a pan-RAR antagonist exhibited opposite effects. Supporting the cell biological data, EVI1 also strongly enhanced atRA regulated gene transcription in LSC enriched cells. These data confirm the previously observed cooperation between EVI1 and atRA in AML, yet in contrast to earlier studies suggest that the main outcome of this interaction is not antileukemic, but leukemia-promoting. Our study is the first to demonstrate that EVI1 enhances essential properties of AML LSCs, and to identify a molecular determinant of the response of AML LSCs to atRA. SOURCE: Rotraud Wieser (rotraud.wieser@meduniwien.ac.at) - Medical University of Vienna