학술논문
The histone demethylase KDM5C functions as a tumor suppressor in AML by repression of bivalently marked immature genes
Document Type
Article
Author
Trempenau, Mette Louise; Schuster, Mikkel Bruhn; Pundhir, Sachin; Pereira, Mafalda Araujo; Kalvisa, Adrija; Tapia, Marta; Su, Jinyu; Ge, Ying; de Boer, Bauke; Balhuizen, Alexander; Bagger, Frederik Otzen; Shliaha, Pavel; Sroczynska, Patrycja; Walfridsson, Julian; Grønbæk, Kirsten; Theilgaard-Mönch, Kim; Jensen, Ole N.; Helin, Kristian; Porse, Bo T.
Source
Leukemia; March 2023, Vol. 37 Issue: 3 p593-605, 13p
Subject
Language
ISSN
08876924; 14765551
Abstract
Epigenetic regulators are frequently mutated in hematological malignancies including acute myeloid leukemia (AML). Thus, the identification and characterization of novel epigenetic drivers affecting AML biology holds potential to improve our basic understanding of AML and to uncover novel options for therapeutic intervention. To identify novel tumor suppressive epigenetic regulators in AML, we performed an in vivo short hairpin RNA (shRNA) screen in the context of CEBPAmutant AML. This identified the Histone 3 Lysine 4 (H3K4) demethylase KDM5C as a tumor suppressor, and we show that reduced Kdm5c/KDM5Cexpression results in accelerated growth both in human and murine AML cell lines, as well as in vivo in Cebpamutant and inv(16) AML mouse models. Mechanistically, we show that KDM5C act as a transcriptional repressor through its demethylase activity at promoters. Specifically, KDM5C knockdown results in globally increased H3K4me3 levels associated with up-regulation of bivalently marked immature genes. This is accompanied by a de-differentiation phenotype that could be reversed by modulating levels of several direct and indirect downstream mediators. Finally, the association of KDM5Clevels with long-term disease-free survival of female AML patients emphasizes the clinical relevance of our findings and identifies KDM5Cas a novel female-biased tumor suppressor in AML.