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Lee HO , He X , Mookerjee-Basu J , Zhongping D , Hua X , Nicolas E , Sulis ML , Ferrando AA , Testa JR , Kappes DJ
Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas
Proc Natl Acad Sci U S A. 2015 Jun 23;112(25) :7773-8
PMID: 26056302    PMCID: PMC4485124    URL: http://www.ncbi.nlm.nih.gov/pubmed/26056302
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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-alphabetaTCR 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.
Lee, Hyung-Ok He, Xiao Mookerjee-Basu, Jayati Zhongping, Dai Hua, Xiang Nicolas, Emmanuelle Sulis, Maria Luisa Ferrando, Adolfo A Testa, Joseph R Kappes, Dietmar J United States Proc Natl Acad Sci U S A. 2015 Jun 23;112(25):7773-8. doi: 10.1073/pnas.1424104112. Epub 2015 Jun 8.