Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas.

in Proceedings of the National Academy of Sciences of the United States of America by Hyung-Ok Lee, Xiao He, Jayati Mookerjee-Basu, Dai Zhongping, Xiang Hua, Emmanuelle Nicolas, Maria Luisa Sulis, Adolfo A Ferrando, Joseph R Testa, Dietmar J Kappes

TLDR

  • The study shows that the transcription factor ThPOK is an oncogene that drives the development of thymic lymphomas in mice, and that TCR signaling and thymocyte development are required for lymphomagenesis.
  • The study provides new insights into the mechanisms of lymphomagenesis and highlights the potential therapeutic targets for the prevention and treatment of T-ALL.

Abstract

The transcription factor T-helper-inducing POZ/Krueppel-like factor (ThPOK, encoded by the Zbtb7b gene) plays widespread and critical roles in T-cell development, particularly as the master regulator of CD4 commitment. Here we show that mice expressing a constitutive T-cell-specific ThPOK transgene (ThPOK(const) mice) develop thymic lymphomas. These tumors resemble human T-cell acute lymphoblastic leukemia (T-ALL), in that they predominantly exhibit activating Notch1 mutations. Lymphomagenesis is prevented if thymocyte development is arrested at the DN3 stage by recombination-activating gene (RAG) deficiency, but restored by introduction of a T-cell receptor (TCR) transgene or by a single injection of anti-αβTCR antibody into ThPOK(const) RAG-deficient mice, which promotes development to the CD4(+)8(+) (DP) stage. Hence, TCR signals and/or traversal of the DN (double negative) > DP (double positive) checkpoint are required for ThPOK-mediated lymphomagenesis. These results demonstrate a novel link between ThPOK, TCR signaling, and lymphomagenesis. Finally, we present evidence that ectopic ThPOK expression gives rise to a preleukemic and self-perpetuating DN4 lymphoma precursor population. Our results collectively define a novel role for ThPOK as an oncogene and precisely map the stage in thymopoiesis susceptible to ThPOK-dependent tumor initiation.

Overview

  • The study examined the role of the ThPOK transcription factor in T-cell development and its potential links to lymphomagenesis.
  • The researchers created mice that express a constitutive T-cell-specific ThPOK transgene and found that these mice develop thymic lymphomas.
  • The study aimed to investigate the relationship between ThPOK, TCR signaling, and lymphomagenesis, and to define the stage in thymopoiesis susceptible to ThPOK-dependent tumor initiation.

Comparative Analysis & Findings

  • The study found that mice expressing a constitutive T-cell-specific ThPOK transgene (ThPOK(const) mice) develop thymic lymphomas, which resemble human T-cell acute lymphoblastic leukemia (T-ALL) in terms of predominantly exhibiting activating Notch1 mutations.
  • The lymphomagenesis was prevented in ThPOK(const) RAG-deficient mice, but restored by introducing a TCR transgene or a single injection of anti-αβTCR antibody, which promotes development to the CD4(+)8(+) (DP) stage.
  • The study found that ectopic ThPOK expression gives rise to a preleukemic and self-perpetuating DN4 lymphoma precursor population.

Implications and Future Directions

  • These findings demonstrate a novel link between ThPOK, TCR signaling, and lymphomagenesis, and suggest that ThPOK is an oncogene.
  • The study highlights the importance of understanding the mechanisms of ThPOK-mediated lymphomagenesis, particularly in the context of TCR signaling and thymocyte development.
  • Future studies could explore the therapeutic potential of targeting ThPOK or its downstream effectors to prevent or treat T-ALL.
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