H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, MRC-4East, Tampa, FL 33612, USA.
Mol Cancer Res. 2010 Jun;8(6):907-18. doi: 10.1158/1541-7786.MCR-10-0131. Epub 2010 Jun 8.
Mantle cell lymphoma (MCL) is an aggressive form of B-cell lymphoma with a poor disease-free survival rate. The proteasome inhibitor bortezomib is approved for the treatment of relapsed and refractory MCL and has efficacy in about 30% of patients. However, the precise mechanism of action of bortezomib is not well understood. This report establishes a requirement for the transcription repressor PR domain zinc finger protein 1 (PRDM1, Blimp1) in the response to bortezomib. Bortezomib rapidly induces transcription of PRDM1 as part of the apoptotic response in both cell lines and primary MCL tumor cells. Knockdown of PRDM1 blocks activation of NOXA and inhibits apoptosis, whereas ectopic expression of PRDM1 alone leads to apoptosis in MCL. Two novel direct targets of PRDM1 were identified in MCL cells: MKI67 (Ki67) and proliferating cell nuclear antigen (PCNA). Both MKI67 and PCNA are required for proliferation and survival. Chromatin immunoprecipitation and knockdown studies reveal that specific repression of MKI67 and PCNA is mediated by PRDM1 in response to bortezomib. Furthermore, promoter studies and mutation/deletion analysis show that PRDM1 functions through specific sites in the PCNA proximal promoter and an MKI67 distal upstream repression domain. Together, these findings establish PRDM1 as a key mediator of bortezomib activity in MCL.
套细胞淋巴瘤（MCL）是一种侵袭性 B 细胞淋巴瘤，无疾病生存预后较差。蛋白酶体抑制剂硼替佐米已被批准用于治疗复发性和难治性 MCL，对约 30%的患者有效。然而，硼替佐米的确切作用机制尚不清楚。本研究报告确立了转录抑制因子 PR 结构域锌指蛋白 1（PRDM1，也称为 Blimp1）在硼替佐米反应中的必要性。硼替佐米在细胞系和原发性 MCL 肿瘤细胞中快速诱导 PRDM1 的转录，作为凋亡反应的一部分。PRDM1 的敲低会阻断 NOXA 的激活并抑制细胞凋亡，而 PRDM1 的异位表达则会导致 MCL 细胞凋亡。在 MCL 细胞中鉴定出 PRDM1 的两个新的直接靶标：MKI67（Ki67）和增殖细胞核抗原（PCNA）。MKI67 和 PCNA 均是增殖和存活所必需的。染色质免疫沉淀和敲低研究表明，硼替佐米诱导的 MKI67 和 PCNA 的特异性抑制是由 PRDM1 介导的。此外，启动子研究和突变/缺失分析表明，PRDM1 通过 PCNA 近端启动子和 MKI67 远端上游抑制结构域中的特定位点发挥作用。总之，这些发现确立了 PRDM1 是 MCL 中硼替佐米活性的关键介质。
