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

Autor: Qu Jiang, Johanna Stachelscheid, Johannes Bloehdorn, Alicja Pacholewska, Christoph Markus Aszyk, Francien Grotenhuijs, Tony Andreas Müller, Ozlem Onder, Prerana Wagle, Carmen Diana Herling, Maria Kleppe, Zhefang Wang, Kevin R. Coombes, Sandra Robrecht, Priya S. Dalvi, Bianca Andra Lungu, Petra Mayer, Lynne V. Abruzzo, Janine Altmüller, Birgit Sybille Gathof, Thorsten Persigehl, Kirsten Fischer, Billy Michael Chelliah Jebaraj, Hugh Young Rienhoff, Rupert C. Ecker, Yue Zhao, Christiane Josephine Bruns, Stephan Stilgenbauer, Kojo S. J. Elenitoba-Johnson, Michael Hallek, Michal R. Schweiger, Margarete Odenthal, Elena Vasyutina, Marco Herling
Rok vydání: 2023
Předmět:
Zdroj: Blood.
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood.2022017230
Popis: In chronic lymphocytic leukemia (CLL), epigenetic alterations are considered to centrally shape the transcriptional signatures that drive disease evolution and that 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 (Kdm1a-KD) in Eμ-TCL1A mice reduced leukemic burden and prolonged animal survival, accompanied by upregulated p53 and pro-apoptotic pathways. Genetic KDM1A depletion also affected milieu components (T-, stromal, monocytic cells), resulting in significant reductions of their capacity to support CLL cell survival and proliferation. Integrated analyses of differential global transcriptomes (RNA-seq) and H3K4me3 marks (ChIP-seq) in Eµ-TCL1A vs. iKdm1aKD;Eµ-TCL1A mice (confirmed in human CLL) implicate KDM1A as an oncogenic transcriptional repressor in CLL by altering histone methylation patterns with pronounced effects on defined cell death and motility pathways. Finally, pharmacologic KDM1A inhibition altered H3K4/9 target methylation and revealed marked anti-B-cell-leukemic synergisms. Overall, we established the pathogenic role and effector networks of KDM1A in CLL, namely via tumor-cell intrinsic mechanisms and impacts in cells of the microenvironment. Our data also provide rationales to further investigate therapeutic KDM1A targeting in CLL.
Databáze: OpenAIRE
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