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

作者：Lee Hyung Ok; He Xiao; Mookerjee Basu Jayati; Dai Zhongping; Hua Xiang; Nicolas Emmanuelle; Sulis Maria Luisa; Ferrando Adolfo A; Testa Joseph R; Kappes Dietmar J^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2015, 112(25): 7773-7778.

DOI：10.1073/pnas.1424104112

• ThPOK
• lymphoma
• thymus
• development
• TCR

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 (ThPOKconst 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-alpha beta TCR antibody into ThPOKconst 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.

• 出版日期2015-6-23