Publication

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

Agger, K., Miyagi, S., Pedersen, M. T., Kooistra, S. M., Johansen, J. V. & Helin, K., 1-Jun-2016, In : Genes & Development. 30, 11, p. 1278-1288 11 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Karl Agger
  • Satoru Miyagi
  • Marianne Terndrup Pedersen
  • Susanne M. Kooistra
  • Jens Vilstrup Johansen
  • Kristian Helin

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 a (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.

Original languageEnglish
Pages (from-to)1278-1288
Number of pages11
JournalGenes & Development
Volume30
Issue number11
Publication statusPublished - 1-Jun-2016

    Keywords

  • acute myeloid leukemia, histone demethylase, H3K9 methylation, JMJD2, epigenetics, interleukin 3, MLL-REARRANGED LEUKEMIA, ACUTE MYELOGENOUS LEUKEMIA, RECEPTOR-ALPHA CHAIN, STEM-CELLS, HISTONE DEMETHYLASES, CANCER, FAMILY, DOT1L, TRIMETHYLATION, IDENTIFICATION

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