Wang Miao, Atayar Cigdem, Rosati Stefano, Bosga-Bouwer Anneke, Kluin Philip, Visser Lydia
Department of Pathology and Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
J Pathol. 2009 May;218(1):95-103. doi: 10.1002/path.2521.
Mantle cell lymphoma (MCL) is characterized by genetic instability and a poor prognosis. Many blastoid variants are (hypo)tetraploid and have an even worse prognosis. We investigated the role of signalling by mitogen-activated protein kinases (MAPKs) in MCL. As compared to normal tonsil B cells, MCL cells showed higher activation of the JNK MAPK in both an MAPK array and a sandwich ELISA assay. Immunohistochemistry showed overexpression of phospho (p)-JNK (Thr183/Tyr185) in 30 of 37 MCL cases. Inhibition of p-JNK with SP600125 resulted in growth arrest in all four MCL cell lines (Jeko-1, HBL-2, UPN-1, Granta-519), which could be partly reversed by the addition of CD40L and IL-4. Furthermore, SP600125 led to G2/M phase arrest on day 1 and a striking increase in endoreduplication on day 2 and day 3, which was confirmed by karyotype analysis. G2/M arrest was associated with down-regulation of EGR1 and p21 protein expression. SP600125-induced polyploidy could be blocked by the BCL-2 inhibitor YC137. These data suggest that constitutive JNK activity is necessary to promote proliferation and maintain diploidy in MCL. JNK inhibition leads to cell cycle deregulation and endoreduplication, mimicking the tetraploid state seen in a subset of MCL cases. Thus, our data also provide an experimental model to study polyploid MCL cells.
套细胞淋巴瘤（MCL）具有遗传不稳定性且预后较差。许多母细胞样变体为（亚）四倍体，预后更差。我们研究了丝裂原活化蛋白激酶（MAPK）信号传导在MCL中的作用。与正常扁桃体B细胞相比，在MAPK阵列和夹心ELISA检测中，MCL细胞均显示出更高的JNK MAPK激活水平。免疫组织化学显示，在37例MCL病例中有30例磷酸化（p）-JNK（Thr183/Tyr185）过表达。用SP600125抑制p-JNK导致所有四种MCL细胞系（Jeko-1、HBL-2、UPN-1、Granta-519）生长停滞，添加CD40L和IL-4可部分逆转这种停滞。此外，SP600125在第1天导致G2/M期停滞，在第2天和第3天导致核内复制显著增加，核型分析证实了这一点。G2/M期停滞与EGR1和p21蛋白表达下调有关。SP60012诱导的多倍体可被BCL-2抑制剂YC137阻断。这些数据表明，组成型JNK活性对于促进MCL增殖和维持二倍体状态是必要的。JNK抑制导致细胞周期失调和核内复制，模拟了一部分MCL病例中所见的四倍体状态。因此，我们的数据还提供了一个研究多倍体MCL细胞的实验模型。
