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, 2015/6/23;112(25):7773-8.
Lee HO[1], He X[2], Mookerjee-Basu J[1], Zhongping D[1], Hua X[1], Nicolas E[1], Sulis ML[3], Ferrando AA[3], Testa JR[1], Kappes DJ[4]
Affiliations
PMID: 26056302DOI: 10.1073/pnas.1424104112
Impact factor: 12.779
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.
Keywords: TCR; ThPOK; development; lymphoma; thymus
MeSH terms
Animals; Gene Expression Regulation; Incidence; Lymphoma, T-Cell; Mice; Receptors, Antigen, T-Cell; Receptors, Notch; Signal Transduction; T-Lymphocytes; Transcription Factors; Transgenes
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