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 7

Correlation between PELI1 and BCL6 expression, and OS according to PELI1 expression, in DLBCL patients.

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Correlation between PELI1 and BCL6 expression, and OS according to PELI1...
(A) Representative images of IHC staining for PELI1 and BCL6 in the same DLBCL specimens. Original magnification, ×400. IHC staining results for PELI1 and BCL6 levels were scored according to the staining intensity, extent, and location of positive tumor cells (calculated only for PELI1). The PELI1hi group was defined as >10% tumor cells showing moderate to strong PELI1 expression equally in cytoplasm and nuclei. (B) Representative images of FISH using the BCL6 break-apart probe on paraffin sections of 113 DLBCL specimens. Each nucleus showed 2 yellow signals (no translocation signal) as well as 1 green signal and 1 red signal, indicative of a translocation signal at the BCL6 locus. Original magnification, ×1,000; ×1,500 (insets). (C and D) Scatter plot representations of correlation between PELI1 and BCL6 expression in BCL6 translocation–negative (n = 87) and BCL6 translocation–positive (n = 26) DLBCL cases. Spearman r and P values are indicated. (E) IHC staining for PELI1 proteins in 113 patients with DLBCLs. PELI1hi cases were defined by intensity (score of 2–3), extent (>10%), and location (score of 3) of PELI1 expression in tumor cells. Kaplan-Meier curve shows OS of PELI1hi (n = 85; 75% of cases) versus PELI1lo (n = 28; 25%) DLBCL patients (P = 0.003, log-rank test).