Hematopathology Section, Laboratory of Pathology, Hospital Clinic de Barcelona, Insititut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
Mod Pathol. 2013 Oct;26(10):1329-37. doi: 10.1038/modpathol.2013.73. Epub 2013 Apr 19.
ALK-positive large B-cell lymphoma is an aggressive lymphoid neoplasm characterized by a monomorphic proliferation of immunoblast-like cells expressing a plasmablastic phenotype and carrying ALK rearrangements. MYC rearrangements are frequent in plasmablastic lymphomas, advanced plasma cell myelomas and a subgroup of diffuse large B-cell lymphomas, but their presence in ALK-positive large B-cell lymphomas is unknown. MYC expression is downregulated by BLIMP1, a master modulator of plasma cell differentiation. BLIMP1 and MYC are upregulated by STAT3, a signal transducer activated by ALK. To determine the role of BLIMP1, MYC and STAT3 in the pathogenesis of ALK-positive large B-cell lymphomas, we investigated MYC rearrangement and the expression of MYC, phosphorylated STAT3, BLIMP1, PAX5 and XBP1 in 12 ALK-positive large B-cell lymphomas. All cases expressed ALK with a granular cytoplasmic pattern. Nine cases had a split signal consistent with an ALK rearrangement. Three additional cases showed a deletion of the 5' or 3' end of the ALK probe consistent with cryptic translocation. PAX5 was virtually negative in all cases tested, whereas BLIMP1 was expressed in all tumors and XBP1 in 11 of 12. Phosphorylated STAT3 was observed in all cases with a strong and diffuse nuclear pattern. MYC rearrangements were not identified in any tumor, but MYC gains and amplification were detected in six cases and one case, respectively. MYC protein was expressed in all tumors independently of MYC gene alterations. These results indicate that ALK-positive large B-cell lymphomas express a complete plasmablastic differentiation program but, contrary to plasmablastic lymphomas, do not have MYC rearrangements. STAT3 is constantly activated and may be an alternative mechanism to promote MYC expression in these tumors. The relevance of the ALK/STAT3 pathway in the pathogenesis of ALK-positive large B-cell lymphomas may offer an attractive target for new therapies.
ALK 阳性大 B 细胞淋巴瘤是一种侵袭性淋巴肿瘤，其特征为表达浆母细胞表型的单形性免疫母细胞样细胞的弥漫性增生，并伴有 ALK 重排。MYC 重排在浆母细胞瘤、高级别浆细胞骨髓瘤和部分弥漫性大 B 细胞淋巴瘤中较为常见，但在 ALK 阳性大 B 细胞淋巴瘤中其存在情况尚不清楚。BLIMP1 是浆细胞分化的主要调节因子，可下调 MYC 的表达。BLIMP1 和 MYC 可被激活 ALK 的信号转导物 STAT3 上调。为了确定 BLIMP1、MYC 和 STAT3 在 ALK 阳性大 B 细胞淋巴瘤发病机制中的作用，我们研究了 12 例 ALK 阳性大 B 细胞淋巴瘤中 MYC 重排以及 MYC、磷酸化 STAT3、BLIMP1、PAX5 和 XBP1 的表达情况。所有病例均表达具有颗粒状细胞质模式的 ALK。9 例病例的信号呈分裂样，提示存在 ALK 重排。另外 3 例病例显示 ALK 探针的 5'或 3'端缺失，提示存在隐匿性易位。所有检测的病例中 PAX5 几乎均为阴性，而 BLIMP1 在所有肿瘤中表达，XBP1 在 12 例中的 11 例中表达。所有病例均观察到磷酸化 STAT3，其具有强而弥漫的核模式。任何肿瘤中均未鉴定出 MYC 重排，但在 6 例和 1 例中分别检测到 MYC 获得和扩增。所有肿瘤均独立于 MYC 基因改变表达 MYC 蛋白。这些结果表明，ALK 阳性大 B 细胞淋巴瘤表达完整的浆母细胞分化程序，但与浆母细胞瘤不同，其并不存在 MYC 重排。STAT3 持续激活，可能是促进这些肿瘤中 MYC 表达的替代机制。ALK/STAT3 通路在 ALK 阳性大 B 细胞淋巴瘤发病机制中的相关性可能为新的治疗方法提供有吸引力的靶点。
