The proto-oncogene TCL1A deregulates cell cycle and genomic stability in CLL

• Published in: Blood 2023-03, Vol.141 (12), p.1425-1441
• Main Authors: Stachelscheid, Johanna, Jiang, Qu, Aszyk, Christoph, Warner, Kathrin, Bley, Nadine, Müller, Tony, Vydzhak, Olga, Symeonidis, Konstantinos, Crispatzu, Giuliano, Mayer, Petra, Blakemore, Stuart James, Goehring, Gudrun, Newrzela, Sebastian, Hippler, Stephanie, Robrecht, Sandra, Kreuzer, Karl-Anton, Pallasch, Christian, Krüger, Marcus, Lechner, Axel, Fischer, Kirsten, Stilgenbauer, Stephan, Beutner, Dirk, Hallek, Michael, Auguin, Daniel, Hüttelmaier, Stefan, Bloehdorn, Johannes, Vasyutina, Elena, Herling, Marco
• Format: Article
• Language: English
• Subjects: Animals; Cell Cycle - genetics; Cell Cycle Proteins - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Lymphoma, B-Cell - genetics; Mice; Mitosis; Proteomics; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogenes
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2022015494

•TCL1A directly engages CDC20 in the mitotic checkpoint complex, accelerating cell cycle transit and driving genome instability in B cells.•Downregulated CDC20 in CLL cells resembles the aneuploidy phenotype and is associated with more aggressive disease and cellular features. [Display omitted] Upregulation of the proto-oncogene T-cell leukemia/lymphoma 1A (TCL1A) is causally implicated in various B-cell and T-cell malignancies. High-level TCL1A correlates with aggressive disease features and inferior clinical outcomes. However, the molecular and cell biological consequences of, particularly nuclear, TCL1A are not fully elucidated. We observed here in mouse models of subcellular site-specific TCL1A-induced lymphomagenesis that TCL1A exerts a strong transforming impact via nuclear topography. In proteomic screens of TCL1A-bound molecules in chronic lymphocytic leukemia (CLL) cells and B-cell lymphoma lines, we identified regulators of cell cycle and DNA repair pathways as novel TCL1A interactors, particularly enriched under induced DNA damage and mitosis. By functional mapping and in silico modeling, we specifically identified the mitotic checkpoint protein, cell division cycle 20 (CDC20), as a direct TCL1A interactor. According to the regulatory impact of TCL1A on the activity of the CDC20-containing mitotic checkpoint and anaphase-promoting complexes during mitotic progression, TCL1A overexpression accelerated cell cycle transition in B-cell lymphoma lines, impaired apoptotic damage responses in association with pronounced chromosome missegregation, and caused cellular aneuploidy in Eμ-TCL1A mice. Among hematopoietic cancers, CDC20 levels seem particularly low in CLL. CDC20 expression negatively correlated with TCL1A and lower expression marked more aggressive and genomically instable disease and cellular phenotypes. Knockdown of Cdc20 in TCL1A-initiated murine CLL promoted aneuploidy and leukemic acceleration. Taken together, we discovered a novel cell cycle–associated effect of TCL1A abrogating controlled cell cycle transition. This adds to our concept of oncogenic TCL1A by targeting genome stability. Overall, we propose that TCL1A acts as a pleiotropic adapter molecule with a synergistic net effect of multiple hijacked pathways. Heightened expression of the proto-oncogene TCL1A is associated with aggressive biology in chronic lymphocytic leukemia (CLL). Using primary CLL cells and murine models, Stachelscheid and colleagues describe the pleiotropic eff