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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

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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 5

PELI1 expression promotes BCL6 stabilization.

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PELI1 expression promotes BCL6 stabilization.
(A) Cellular extracts from...
(A) Cellular extracts from 9 B cell lymphoma cell lines were immunoblotted with the indicated antibodies. (B) DOHH2 cells were transfected with control luciferase shRNA (shLuc), PELI1 shRNA (shPELI1; targeting PELI1 ORF), or 3′ untranslated region PELI1 shRNA (3′UTR; targeting PELI1 3′UTR) encoding construct in combination with the GFP or GFP-PELI1 expression plasmid, and SU-DHL4 cells were transfected with the pMyc or pMyc-PELI1 expression plasmid in combination with the shLuc or 3′UTR encoding construct. (C) HeLa cells were transfected with control pMyc, pMyc-PELI1-FL, or pMyc-PELI1-ΔC and HA-BCL6. At 24 hours after transfection, cells were cultured in the presence of LPS, further treated with cycloheximide (CHX), and lysed at the indicated times. (D) Splenic B220+ cells were isolated from non-Tg and PELI1-Tg mice and maintained in the absence or presence of LPS. At 24 hours after treatment, splenic B220+ cells were lysed and subjected to immunoblotting. In B–D, expression levels relative to the respective control are shown below blots. (E) B220+ cells were isolated from BM, LNs, and spleen of non-Tg and PELI1-Tg mice and maintained in the presence of LPS. B220+ cells were subjected to the intracellular staining of BCL2hi cells and BCL6hi cells. Gray area indicates isotype control staining. (F) Quantification of the BCL6hi cell population in the BM, LNs, and spleen by intracellular staining of non-Tg and PELI1-Tg mouse–derived B220+ cells. Data (mean ± SEM) are representative of 2 experiments with 3 mice per experiment. ***P < 0.001.
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