TRIB2, a serine/threonine pseudokinase identified as an oncogene, is expressed at high levels in the T-cell compartment of hematopoiesis. The proliferation of developing thymocytes is tightly controlled to prevent leukemic transformation of T cells. Here we examine Trib2 loss in murine hematopoiesis under steady state and proliferative stress conditions, including genotoxic and oncogenic stress. Trib2-/- developing thymocytes show increased proliferation, and Trib2-/- mice have significantly higher thymic cellularity at steady state. During stress hematopoiesis, Trib2-/- developing thymocytes undergo accelerated proliferation and demonstrate hypersensitivity to 5-fluorouracil (5-FU)-induced cell death. Despite the increased cell death post 5-FU-induced proliferative stress, Trib2-/- mice exhibit accelerated thymopoietic recovery post treatment due to increased cell division kinetics of developing thymocytes. The increased proliferation in Trib2-/- thymocytes was exacerbated under oncogenic stress. In an experimental murine T-cell acute lymphoblastic leukemia (T-ALL) model, Trib2-/- mice had reduced latency in vivo, which associated with impaired MAP kinase (MAPK) activation. High and low expression levels of Trib2 correlate with immature and mature subtypes of human T-ALL, respectively, and associate with MAPK. Thus, TRIB2 emerges as a novel regulator of thymocyte cellular proliferation, important for the thymopoietic response to genotoxic and oncogenic stress, and possessing tumor suppressor function.
CITATION STYLE
Liang, K. L., O’Connor, C., Veiga, J. P., McCarthy, T. V., & Keeshan, K. (2016). TRIB2 regulates normal and stress-induced thymocyte proliferation. Cell Discovery, 2. https://doi.org/10.1038/celldisc.2015.50
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