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 3

BMT of HSCs expressing PELI1 results in development of lymphoid tumors with B cell infiltration.

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BMT of HSCs expressing PELI1 results in development of lymphoid tumors w...
(A) BMT protocol. HSCs derived from primary murine BM were retrovirally transduced with GFP or GFP-PELI1, subjected to 3 consecutive rounds of transduction, and transplanted into sublethally irradiated recipient mice (see Supplemental Methods for details). (B) Flow cytometric quantification of the GFP+ cell population in blood, LN, and BM of GFP or GFP-PELI1 recipient mice 25–30 weeks after BMT. (C and D) Representative macroscopic images showing thymic tumors and enlarged LNs of GFP-PELI1 recipient mice. Eμ-Myc-Tg mice were used as a positive control for lymphomagenesis. Ax, axillary; In, inguinal. (E) Representative flow cytometric analysis results for B220+ and CD3+ cell populations in the thymus of GFP and GFP-PELI1 recipient mice as well as Eμ-Myc-Tg mice. (F) Representative flow cytometric analysis for B220+ and CD3+ cell populations in LNs of GFP and GFP-PELI1 recipient mice. Ce, cervical. (G) Flow cytometric quantification of B220+ and CD3+ cell populations in LNs of control GFP (n = 4) and GFP-PELI1 (n = 5) recipient mice at 30 weeks after BMT (data represent mean ± SEM). *P < 0.05, **P < 0.01. (H) Representative images of IHC analyses for B220 antigen expression in LN and thymic tissue samples isolated from GFP and GFP-PELI1 recipient mice as well as Eμ-Myc-Tg mice. Original magnification, ×200; Scale bars: 200 μm.