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Proc Natl Acad Sci U S A. 2015 Jun 23;112(25):7773-8. doi: 10.1073/pnas.1424104112. Epub 2015 Jun 8.

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

Author information

1
Fox Chase Cancer Center, Philadelphia, PA 19111;
2
University of Utah, Salt Lake City, UT 84112;
3
Institute of Cancer Genetics, Columbia University, New York, NY 10032.
4
Fox Chase Cancer Center, Philadelphia, PA 19111; Dietmar.Kappes@fccc.edu.

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

PMID:
26056302
PMCID:
PMC4485124
DOI:
10.1073/pnas.1424104112
[Indexed for MEDLINE]
Free PMC Article

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