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

Genes Dev. 2016 Jun 1;30(11):1278-88. doi: 10.1101/gad.280495.116. Epub 2016 Jun 2.


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.

Keywords: H3K9 methylation; JMJD2; acute myeloid leukemia; epigenetics; histone demethylase; interleukin 3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Tamoxifen / analogs & derivatives
  • Tamoxifen / pharmacology
  • Tamoxifen / therapeutic use


  • Interleukin-3 Receptor alpha Subunit
  • Tamoxifen
  • afimoxifene
  • Jumonji Domain-Containing Histone Demethylases