Hye-Young Park1, Heounjeong Go2, Ha Rim Song3, Suhyeon Kim1, Geun-Hyoung Ha1, Yoon-Kyung Jeon4, Ji-Eun Kim5, Ho Lee6, Hyeseong Cho7, Ho Chul Kang8, Hee-Young Chung9, Chul-Woo Kim4, Doo Hyun Chung4 and Chang-Woo Lee1,3
1Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
2Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
3Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Suwon, Republic of Korea.
4Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.
5Department of Pathology, Seoul Metropolitan Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea.
6Research Institute, National Cancer Center, Goyang, Republic of Korea.
7Department of Biochemistry and Molecular Biology and
8Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.
9Department of Microbiology, Hanyang University College of Medicine, Seoul, Republic of Korea.
Address correspondence to: Chang-Woo Lee, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea.
Authorship note: Hye-Young Park and Heounjeong Go contributed equally to this work.
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.