Pellino 1 promotes lymphomagenesis by deregulating BCL6 polyubiquitination
Hye-Young Park, … , Doo Hyun Chung, Chang-Woo Lee
Hye-Young Park, … , Doo Hyun Chung, Chang-Woo Lee
Published October 8, 2014
Citation Information: J Clin Invest. 2014;124(11):4976-4988. https://doi.org/10.1172/JCI75667.
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Pellino 1 promotes lymphomagenesis by deregulating BCL6 polyubiquitination

Abstract

The signal-responsive E3 ubiquitin ligase pellino 1 (PELI1) regulates TLR and T cell receptor (TCR) signaling and contributes to the maintenance of autoimmunity; however, little is known about the consequence of mutations that result in upregulation of PELI1. Here, we developed transgenic mice that constitutively express human PELI1 and determined that these mice have a shorter lifespan due to tumor formation. Constitutive expression of PELI1 resulted in ligand-independent hyperactivation of B cells and facilitated the development of a wide range of lymphoid tumors, with prominent B cell infiltration observed across multiple organs. PELI1 directly interacted with the oncoprotein B cell chronic lymphocytic leukemia (BCL6) and induced lysine 63–mediated BCL6 polyubiquitination. In samples from patients with diffuse large B cell lymphomas (DLBCLs), PELI1 expression levels positively correlated with BCL6 expression, and PELI1 overexpression was closely associated with poor prognosis in DLBCLs. Together, these results suggest that increased PELI1 expression and subsequent induction of BCL6 promotes lymphomagenesis and that this pathway may be a potential target for therapeutic strategies to treat B cell lymphomas.

Authors

Hye-Young Park, Heounjeong Go, Ha Rim Song, Suhyeon Kim, Geun-Hyoung Ha, Yoon-Kyung Jeon, Ji-Eun Kim, Ho Lee, Hyeseong Cho, Ho Chul Kang, Hee-Young Chung, Chul-Woo Kim, Doo Hyun Chung, Chang-Woo Lee

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Figure 2

Constitutive PELI1 expression promotes hematopoietic alterations and activates ligand-independent B cell signal transduction.

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Constitutive PELI1 expression promotes hematopoietic alterations and act...
(A) Proportion of B220+ B cell and CD3+ T cell populations, measured by flow cytometry, in cells isolated from spleen, LN, and thymus of non-Tg and PELI1-Tg mice at 14–16 months of age. Data (mean ± SEM) are representative of 3 independent experiments, with 4 mice per experiment. ***P < 0.001. (B) Flow cytometry of CD86 and MHC class II surface expression in splenic cells derived from non-Tg and PELI1-Tg mice incubated in vitro for 24 hours in the presence of anti-CD40 and anti-IgM antibodies. Gray histograms represent untreated non-Tg cells (unstimulated control). (C) Representative images of H&E staining and IHC analyses for B220, CD3, CD20, and CD23 antigen expression in splenic and thymic tissue samples isolated from non-Tg and PELI1-Tg mice. Strong B220 and CD20 staining was observed in the spleen and thymus of PELI1-Tg mice, whereas B220 and CD20 staining was detectable only at the GC of control non-Tg mice. Original magnification, ×200. (D) Liver and lung tissue samples isolated from non-Tg littermates and PELI1-Tg mice were fixed and stained with anti-B220, anti-CD3, anti-CD20, anti-CD23, and anti-Ki67 antibodies in serial sections. Original magnification, ×200.