TRIB2 regulates normal and stress-induced thymocyte proliferation

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Abstract

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.

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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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