title: Jmjd2/Kdm4 demethylases are required for expression of Il3ra and survival of acute myeloid leukemia cells.
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.
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark; Centre for Epigenetics, University of Copenhagen, 2200 Copenhagen, Denmark;
authors.forename: Karl
authors.initials: K
authors.lastname: Agger
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark; Centre for Epigenetics, University of Copenhagen, 2200 Copenhagen, Denmark; The Danish Stem Cell Center (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyagi
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark; Centre for Epigenetics, University of Copenhagen, 2200 Copenhagen, Denmark;
authors.forename: Marianne Terndrup
authors.initials: MT
authors.lastname: Pedersen
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark; Centre for Epigenetics, University of Copenhagen, 2200 Copenhagen, Denmark;
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Kooistra
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark;
authors.forename: Jens Vilstrup
authors.initials: JV
authors.lastname: Johansen
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark; Centre for Epigenetics, University of Copenhagen, 2200 Copenhagen, Denmark; The Danish Stem Cell Center (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Kristian
authors.identifier: 0000-0003-1975-6097
authors.initials: K
authors.lastname: Helin
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053650:Interleukin-3 Receptor alpha Subunit / Q000235:genetics* / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology*; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D053650:Interleukin-3 Receptor alpha Subunit; D013629:Tamoxifen; C016601:afimoxifene; D056484:Jumonji Domain-Containing Histone Demethylases
keywords: H3K9 methylation; JMJD2; acute myeloid leukemia; epigenetics; histone demethylase; interleukin 3