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Prolyl 4-Hydroxylase 2 Promotes B-cell Lymphoma Progression via Hydroxylation of Carabin

Wei Jiang, Xiaoyan Zhou, Zengxia Li, Kaiyu Liu, Weige Wang, Renke Tan, Xiaoji Cong, Jiaoyu Shan, Yanxia Zhan, Zhaomeng Cui, Lizhi Jiang, Quanfu Li, Suqin Shen, Meirong Bai, Yunfeng Cheng, Bin Li, Minjia Tan, Dengke K. Ma, Jun O. Liu and Yongjun Dang

Key points

  • P4HA2 is associated with progression and poor overall survival in DLBCL patients, and could be served as a novel biomarker and therapeutic target.

  • P4HA2 counteracts the negative effect of Carabin on lymphoma by hydroxylation of Carabin at Pro306.

Abstract

B-cell lymphomas are heterogeneous blood disorders with limited therapeutic options, largely because of its propensity to relapse and become refractory to treatments. Carabin, a key suppressor of B cell receptor signaling and proliferation, is inactivated in B-cell lymphoma by unknown mechanisms. Here we identify P4HA2 (Prolyl 4-Hydroxylase 2) as a specific proline hydroxylase of Carabin. Carabin hydroxylation leads to its proteasomal degradation, thereby activating the Ras/ERK pathway and increasing B-cell lymphoma proliferation. P4HA2 is undetectable in normal B cells but up-regulated in the diffuse large B-cell lymphoma (DLBCL), driving Carabin inactivation and lymphoma proliferation. Our results indicate that P4HA2 is a potential prognosis marker for DLBCL and a promising pharmacological target for developing treatment of molecularly stratified B-cell lymphomas.

  • Submitted July 28, 2017.
  • Accepted January 22, 2018.