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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Research Article Vascular biology

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 6

Characterization of B cell lymphomas generated in PELI1-Tg mice.

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Characterization of B cell lymphomas generated in PELI1-Tg mice. (A) Flo...
(A) Flow cytometric analysis of B220, IgM, and IgD surface expression in BM cells isolated from 14-month-old non-Tg and PELI1-Tg mice. B220+-gated pre–B cell (Pre-B; IgM–IgD–), immature B cell (Imm-B; IgM+IgD–), and mature B cell (M-B; IgMloIgD+) cell populations are shown. (B) Flow cytometric analysis of B220, IgM, and CD43 surface expression in BM cells from non-Tg and PELI1-Tg mice. CD43–-gated pre–B cell (B220+IgM–), immature B cell (B220loIgM+), and mature B cell (B220hiIgM+) populations are shown. Data are representative of 3 independent experiments. (C) Representative images of IHC analyses for BCL6, CD10, and MUM1 antigen expression in splenic, thymic, liver, and lung tissue samples isolated from non-Tg and PELI1-Tg mice. Original magnification, ×200; Scale bars: 200 μm.