Jmjd2/Kdm4 demethylases are required for expression of Il3ra and survival of acute myeloid leukemia cells
- Karl Agger1,2,
- Satoru Miyagi1,2,3,4,
- Marianne Terndrup Pedersen1,2,
- Susanne M. Kooistra1,2,5,
- Jens Vilstrup Johansen1 and
- Kristian Helin1,2,3
- 1Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark;
- 2Centre for Epigenetics, University of Copenhagen, 2200 Copenhagen, Denmark;
- 3The Danish Stem Cell Center (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Corresponding author: kristian.helin{at}bric.ku.dk
Abstract
Acute myeloid leukemias (AMLs) with a rearrangement of the mixed-linage leukemia (MLL) gene are aggressive hematopoietic malignancies. Here, we explored the feasibility of using the H3K9- and H3K36-specific demethylases Jmjd2/Kdm4 as putative drug targets in MLL-AF9 translocated leukemia. Using Jmjd2a, Jmjd2b, and Jmjd2c conditional triple-knockout mice, we show that Jmjd2/Kdm4 activities are required for MLL-AF9 translocated AML in vivo and in vitro. We demonstrate that expression of the interleukin 3 receptor α (Il3ra also known as Cd123) subunit is dependent on Jmjd2/Kdm4 through a mechanism involving removal of H3K9me3 from the promoter of the Il3ra gene. Importantly, ectopic expression of Il3ra in Jmjd2/Kdm4 knockout cells alleviates the requirement of Jmjd2/Kdm4 for the survival of AML cells, showing that Il3ra is a critical downstream target of Jmjd2/Kdm4 in leukemia. These results suggest that the JMJD2/KDM4 proteins are promising drug targets for the treatment of AML.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.280495.116.
- Received March 6, 2016.
- Accepted May 4, 2016.
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