TY - JOUR

T1 - The histone demethylase KDM5C functions as a tumor suppressor in AML by repression of bivalently marked immature genes

AU - Trempenau, Mette Louise

AU - Schuster, Mikkel Bruhn

AU - Pundhir, Sachin

AU - Pereira, Mafalda Araujo

AU - Kalvisa, Adrija

AU - Tapia, Marta

AU - Su, Jinyu

AU - Ge, Ying

AU - de Boer, Bauke

AU - Balhuizen, Alexander

AU - Bagger, Frederik Otzen

AU - Shliaha, Pavel

AU - Sroczynska, Patrycja

AU - Walfridsson, Julian

AU - Grønbæk, Kirsten

AU - Theilgaard-Mönch, Kim

AU - Jensen, Ole N

AU - Helin, Kristian

AU - Porse, Bo T

N1 - © 2023. The Author(s).

PY - 2023

Y1 - 2023

N2 - 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 CEBPA mutant AML. This identified the Histone 3 Lysine 4 (H3K4) demethylase KDM5C as a tumor suppressor, and we show that reduced Kdm5c/KDM5C expression results in accelerated growth both in human and murine AML cell lines, as well as in vivo in Cebpa mutant 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 KDM5C levels with long-term disease-free survival of female AML patients emphasizes the clinical relevance of our findings and identifies KDM5C as a novel female-biased tumor suppressor in AML.

AB - 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 CEBPA mutant AML. This identified the Histone 3 Lysine 4 (H3K4) demethylase KDM5C as a tumor suppressor, and we show that reduced Kdm5c/KDM5C expression results in accelerated growth both in human and murine AML cell lines, as well as in vivo in Cebpa mutant 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 KDM5C levels with long-term disease-free survival of female AML patients emphasizes the clinical relevance of our findings and identifies KDM5C as a novel female-biased tumor suppressor in AML.

U2 - 10.1038/s41375-023-01810-6

DO - 10.1038/s41375-023-01810-6

M3 - Journal article

C2 - 36631623

VL - 37

JO - Leukemia

JF - Leukemia

SN - 0887-6924

ER -