Oncogenic role and target properties of the lysine-specific demethylase KDM1A in chronic lymphocytic leukemia

作者：Qu Jiang, Johanna Stachelscheid, Johannes Bloehdorn, Alicja Pacholewska, Christoph Markus Aszyk, Francien Grotenhuijs, Tony Andreas Müller, Özlem Önder, Prerana Wagle, Carmen Herling, Maria Kleppe, Zhefang Wang, Kevin R. Coombes, Sandra Robrecht, Priya Dalvi, Bianca Andra Lungu, Petra Mayer, Lynne V. Abruzzo, Janine Altmüller, Birgit Gathof, Thorsten Persigehl, Kirsten Fischer, Billy Michael Chelliah Jebaraj, Hugh Young Rienhoff, Rupert Ecker, Yue Zhao, Christiane J. Bruns, Stephan Stilgenbauer, Kojo S.J. Elenitoba‐Johnson, Michael Hallek, Michal R. Schweiger, Margarete Odenthal, Elena Vasyutina, Marco Herling · 发表于：Blood · 年份：2023 · DOI：10.1182/blood.2022017230 · 被引用次数：11 · 研究领域：Chronic Lymphocytic Leukemia Research、Histone Deacetylase Inhibitors Research、T-cell and Retrovirus Studies

In chronic lymphocytic leukemia (CLL), epigenetic alterations are considered to centrally shape the transcriptional signatures that drive disease evolution and underlie its biological and clinical subsets. Characterizations of epigenetic regulators, particularly histone-modifying enzymes, are very rudimentary in CLL. In efforts to establish effectors of the CLL-associated oncogene T-cell leukemia 1A (TCL1A), we identified here the lysine-specific histone demethylase KDM1A to interact with the TCL1A protein in B cells in conjunction with an increased catalytic activity of KDM1A. We demonstrate that KDM1A is upregulated in malignant B cells. Elevated KDM1A and associated gene expression signatures correlated with aggressive disease features and adverse clinical outcomes in a large prospective CLL trial cohort. Genetic Kdm1a knockdown in Eμ-TCL1A mice reduced leukemic burden and prolonged animal survival, accompanied by upregulated p53 and proapoptotic pathways. Genetic KDM1A depletion also affected milieu components (T, stromal, and monocytic cells), resulting in significant reductions in their capacity to support CLL-cell survival and proliferation. Integrated analyses of differential global transcriptomes (RNA sequencing) and H3K4me3 marks (chromatin immunoprecipitation sequencing) in Eμ-TCL1A vs iKdm1aKD;Eμ-TCL1A mice (confirmed in human CLL) implicate KDM1A as an oncogenic transcriptional repressor in CLL which alters histone methylation patterns with pronounced effects on ...