title: Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas.
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.
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111;
authors.forename: Hyung-Ok
authors.initials: HO
authors.lastname: Lee
authors.affiliation: University of Utah, Salt Lake City, UT 84112;
authors.forename: Xiao
authors.initials: X
authors.lastname: He
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111;
authors.forename: Jayati
authors.initials: J
authors.lastname: Mookerjee-Basu
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111;
authors.forename: Dai
authors.initials: D
authors.lastname: Zhongping
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111;
authors.forename: Xiang
authors.initials: X
authors.lastname: Hua
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111;
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Nicolas
authors.affiliation: Institute of Cancer Genetics, Columbia University, New York, NY 10032.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Sulis
authors.affiliation: Institute of Cancer Genetics, Columbia University, New York, NY 10032.
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111;
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Testa
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111; Dietmar.Kappes@fccc.edu.
authors.forename: Dietmar J
authors.initials: DJ
authors.lastname: Kappes
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D015994:Incidence; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000473:pathology*; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*; D014157:Transcription Factors / Q000235:genetics*; D019076:Transgenes
chemical_list: D011948:Receptors, Antigen, T-Cell; D051880:Receptors, Notch; D014157:Transcription Factors; C497211:Zbtb7b protein, mouse
keywords: TCR; ThPOK; development; lymphoma; thymus