Guiter Chrystelle, Dusanter-Fourt Isabelle, Copie-Bergman Christiane, Boulland Marie-Laure, Le Gouvello Sabine, Gaulard Philippe, Leroy Karen, Castellano Flavia
U617, INSERM, Université Paris XII/Département de Pathologie, Hôpital Henri Mondor, AP-HP, 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France.
Blood. 2004 Jul 15;104(2):543-9. doi: 10.1182/blood-2003-10-3545. Epub 2004 Mar 25.
Primary mediastinal large B-cell lymphoma (PMBL), currently recognized as a diffuse large B-cell lymphoma (DLBCL) subtype, shows increased expression of interleukin 4 (IL-4)/IL-13 signaling effectors and targets, suggesting constitutive activation of these pathways. We therefore investigated the functional state of the signal transducer and activator of transcription 6 (STAT6), mediating IL-4/IL-13 transcriptional effects. Constitutive STAT6 phosphorylation and DNA-binding activity were detected in PMBL cell lines but not DLBCL cell lines. Moreover, immunohistochemical analysis revealed nuclear phosphorylated STAT6 (P-STAT6) in 8 of 11 PMBL, compared with 1 of 10 DLBCL primary tumors (P =.01). IL-4 and IL-13 transcripts were absent in PMBL cell lines and expressed at low levels in tumors, indicating that, contrary to classical Hodgkin lymphoma (cHL), STAT6 activation is not due to an autocrine IL-4/IL-13 secretion. We demonstrated an amplification of the JAK2 gene in 2 of 6 PMBL cases, and showed higher JAK2 mRNA levels in PMBL compared with DLBCL (P =.005). The Janus kinase 2 (JAK2) was constitutively phosphorylated in the PMBL MedB1 cell line. MedB1 treatment with JAK2 inhibitor AG490 partially decreased STAT6 phosphorylation, suggesting that JAK2 is partially involved in STAT6 activation in these cells. Our findings highlight phosphorylated STAT6 as a characteristic distinguishing PMBL from DLBCL, but a common feature to PMBL and cHL, supporting the hypothesis of common pathogenic events in these 2 lymphomas.
原发性纵隔大B细胞淋巴瘤（PMBL）目前被认为是弥漫性大B细胞淋巴瘤（DLBCL）的一种亚型，其白细胞介素4（IL-4）/IL-13信号效应器和靶标的表达增加，提示这些信号通路的组成性激活。因此，我们研究了介导IL-4/IL-13转录效应的信号转导和转录激活因子6（STAT6）的功能状态。在PMBL细胞系中检测到组成性的STAT6磷酸化和DNA结合活性，而在DLBCL细胞系中未检测到。此外，免疫组织化学分析显示，11例PMBL中有8例存在核磷酸化STAT6（P-STAT6），而10例DLBCL原发性肿瘤中仅有1例出现（P = 0.01）。PMBL细胞系中未检测到IL-4和IL-13转录本，肿瘤中其表达水平较低，这表明与经典霍奇金淋巴瘤（cHL）不同，STAT6激活并非由于自分泌IL-4/IL-13。我们在6例PMBL病例中的2例中发现JAK2基因扩增，并且与DLBCL相比，PMBL中的JAK2 mRNA水平更高（P = 0.005）。在PMBL MedB1细胞系中，Janus激酶2（JAK2）发生组成性磷酸化。用JAK2抑制剂AG490处理MedB1可部分降低STAT6磷酸化，提示JAK2部分参与这些细胞中STAT6的激活。我们的研究结果突出了磷酸化STAT6是区分PMBL与DLBCL的一个特征，但却是PMBL和cHL的一个共同特征，支持了这两种淋巴瘤存在共同致病事件的假说。
