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

Cell Death Dis 2019 Dec 10;10(12):944. Epub 2019 Dec 10.

Division of Oncology, Clinic of Medicine I, Medical University of Vienna, Vienna, Austria.

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 AML. atRA further augmented these effects in an Evi1 dependent manner. EVI1 also strongly enhanced atRA regulated gene transcription in LSC enriched cells. One of their jointly regulated targets, Notch4, was an important mediator of their effects on leukemic stemness. In vitro exposure of leukemic cells to a pan-RAR antagonist caused effects opposite to those of atRA. In vivo antagonist treatment delayed leukemogenesis and reduced LSC abundance, quiescence, and activity in Evi1 AML. Key results were confirmed in human myeloid cell lines retaining some stem cell characteristics as well as in primary human AML samples. In summary, our study is the first to report the importance of EVI1 for key properties of AML LSCs. Furthermore, it shows that atRA enhances, and a pan-RAR antagonist counteracts, the effects of EVI1 on AML stemness, thus raising the possibility of using RAR antagonists in the therapy of EVI1 AML.

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-019-2172-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904467PMC
December 2019

Publication Analysis

Top Keywords

evi1 aml
12
pan-rar antagonist
12
evi1
10
report evi1
8
aml lscs
8
activity evi1
8
myeloid leukemia
8
leukemic cells
8
aml
8
effects evi1
8
cell lines
8
quiescence activity
8
abundance quiescence
8
stem cell
8
acute myeloid
8
retinoic acid
8
enhances pan-rar
8
all-trans retinoic
8
antagonist counteracts
8
effects
5

References

(Supplied by CrossRef)

R Zagozdzon et al.
Contemp. Oncol. (Pozn.) 2015

D Grimwade et al.
Blood 2016

E Papaemmanuil et al.
N. Engl. J. Med. 2016

A Krivtsov et al.
Leukemia 2013

A Krivtsov et al.
Nature 2006

K Haas et al.
Genes Chromosomes Cancer 2008

S Groschel et al.
J. Clin. Oncol. 2010

S Groschel et al.
J. Clin. Oncol. 2013

E Bard-Chapeau et al.
Proc. Natl. Acad. Sci. USA 2012

C Glass et al.
PLoS ONE 2013

K Kataoka et al.
J. Exp. Med. 2011

Similar Publications