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Oncogenic role and target properties of the lysine-specific demethylase KDM1A in chronic lymphocytic leukemia.
Jiang, Qu; Stachelscheid, Johanna; Bloehdorn, Johannes; Pacholewska, Alicja; Aszyk, Christoph; Grotenhuijs, Francien; Müller, Tony; Onder, Ozlem; Wagle, Prerana; Herling, Carmen D; Kleppe, Maria; Wang, Zhefang; Coombes, Kevin R; Robrecht, Sandra; Dalvi, Priya S; Plosnita, Bianca; Mayer, Petra; Abruzzo, Lynne V; Altmüller, Janine; Gathof, Birgit; Persigehl, Thorsten; Fischer, Kirsten; Jebaraj, Billy; Rienhoff, Hugh Y; Ecker, Rupert; Zhao, Yue; Bruns, Christiane J; Stilgenbauer, Stephan; Elenitoba-Johnson, Kojo; Hallek, Michael; Schweiger, Michal R; Odenthal, Margarete; Vasyutina, Elena; Herling, Marco.
Affiliation
  • Jiang Q; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf, University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Stachelscheid J; Cologne Excellence Cluster on Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
  • Bloehdorn J; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
  • Pacholewska A; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf, University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Aszyk C; Cologne Excellence Cluster on Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
  • Grotenhuijs F; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
  • Müller T; Department III of Internal Medicine, Ulm University, Ulm, Germany.
  • Onder O; Institute for Translational Epigenetics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Wagle P; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf, University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Herling CD; Cologne Excellence Cluster on Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
  • Kleppe M; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
  • Wang Z; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf, University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Coombes KR; Cologne Excellence Cluster on Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
  • Robrecht S; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
  • Dalvi PS; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf, University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Plosnita B; Cologne Excellence Cluster on Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
  • Mayer P; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
  • Abruzzo LV; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • Altmüller J; Cologne Excellence Cluster on Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
  • Gathof B; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf, University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Persigehl T; Cologne Excellence Cluster on Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
  • Fischer K; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
  • Jebaraj B; Department of Hematology, Cellular Therapy, and Hemostaseology, University of Leipzig, Leipzig, Germany.
  • Rienhoff HY; Imago Biosciences Inc, San Francisco, CA.
  • Ecker R; Department of General, Visceral, Tumor and Transplantation Surgery, University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Zhao Y; Department of Plastic and Reconstruction Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • Bruns CJ; Department of Population Health Sciences, Division of Biostatistics and Data Science, Georgia Cancer Center at Augusta University, Augusta, GA.
  • Stilgenbauer S; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf, University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Elenitoba-Johnson K; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
  • Hallek M; Institute for Pathology, University Hospital Cologne, Cologne, Germany.
  • Schweiger MR; TissueGnostics Romania SRL, Iasi, Romania.
  • Odenthal M; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf, University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Vasyutina E; Cologne Excellence Cluster on Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
  • Herling M; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Blood ; 142(1): 44-61, 2023 07 06.
Article in En | MEDLINE | ID: mdl-37023372
ABSTRACT
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 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 via tumor-cell intrinsic mechanisms and its impacts in cells of the microenvironment. Our data also provide rationales to further investigate therapeutic KDM1A targeting in CLL.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Leukemia, Lymphocytic, Chronic, B-Cell Type of study: Observational_studies / Risk_factors_studies Limits: Animals / Humans Language: En Journal: Blood Year: 2023 Type: Article Affiliation country: Germany

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Leukemia, Lymphocytic, Chronic, B-Cell Type of study: Observational_studies / Risk_factors_studies Limits: Animals / Humans Language: En Journal: Blood Year: 2023 Type: Article Affiliation country: Germany