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

• Published in: Genes & development Vol. 30; no. 11; pp. 1278 - 1288
• Main Authors: Agger, Karl, Miyagi, Satoru, Pedersen, Marianne Terndrup, Kooistra, Susanne M., Johansen, Jens Vilstrup, Helin, Kristian
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.06.2016
• Subjects: Animals; Cell Differentiation - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell Survival - genetics; Disease Models, Animal; Gene Expression Regulation, Neoplastic - drug effects; Interleukin-3 Receptor alpha Subunit - genetics; Interleukin-3 Receptor alpha Subunit - metabolism; Jumonji Domain-Containing Histone Demethylases - antagonists & inhibitors; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - metabolism; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - enzymology; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - physiopathology; Methylation; Mice; Mice, Knockout; Protein Binding; Research Paper; Tamoxifen - analogs & derivatives; Tamoxifen - pharmacology; Tamoxifen - therapeutic use; JMJD2; acute myeloid leukemia; interleukin 3; histone demethylase; epigenetics; H3K9 methylation
• ISSN: 0890-9369; 1549-5477; 1549-5477
• DOI: 10.1101/gad.280495.116

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.