Article open access publication

Jmjd2/Kdm4 demethylases are required for expression of Il3ra and survival of acute myeloid leukemia cells

Genes & Development, Cold Spring Harbor Laboratory, ISSN 0890-9369

Volume 30, 11, 2016

DOI:10.1101/gad.280495.116, Dimensions: pub.1060407289, PMC: PMC4911927, PMID: 27257215,

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  1. (1) University of Copenhagen, grid.5254.6, KU

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Denmark

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Europe

Description

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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University of Copenhagen

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Times Cited: 37

Field Citation Ratio (FCR): 9.57

Relative Citation ratio (RCR): 1.73

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Hybrid