Wang Wei-Ge, Cui Wen-Li, Wang Lei, Zhu Fen, Wan Xiao-Chun, Ping Bo, Zhou Xiao-Yan, Li Xiao-Qiu
*Department of Pathology, Fudan University Shanghai Cancer Center †Department of Oncology, Shanghai Medical College §Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai ‡Department of Pathology, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, P.R. China.
Am J Surg Pathol. 2015 Jul;39(7):902-11. doi: 10.1097/PAS.0000000000000396.
B-cell receptor (BCR) signaling is crucial for the survival of normal and neoplastic B cells, and inhibitors targeting BCR signaling pathways have shown promising therapeutic outcomes for patients with B-cell lymphomas. In the current study, we analyzed de novo diffuse large B-cell lymphoma without BCR expression (DLBCL, BCR) in 25 cases to determine the BCR/phosphatidylinositol-3-kinase/AKT (BCR/PI3K/AKT) signaling status, clinicopathologic features, and underlying causes leading to the loss of BCR. On the basis of clinical features, 15 (60%) DLBCL, BCR patients were classified into the low-risk group, and 18 (86%) experienced complete remission. Morphologically and immunophenotypically, DLBCL, BCR demonstrated centroblastic cytology (21/25, 84%) and germinal center B-cell-like cell origin (18/25, 72%). Other components in BCR complexity remained intact, on the basis of immunohistochemical findings. Epstein-Barr virus infection, deficiency in B-lineage transcription factors (PAX5, Oct-2, and Bob.1), and oncogene rearrangement did not seem to be associated with BCR loss. The activated form of signaling proteins (pSYK and pAKT) involved in the BCR/PI3K/AKT pathway were expressed at low levels in DLBCL, BCR tissue. In vitro validation revealed that in DLBCL, BCR cell lines, the BCR/PI3K/AKT pathway did not respond to BCR stimulation or inhibition. Our findings suggest that DLBCL, BCR was characterized by a silent BCR/PI3K/AKT pathway, germinal center phenotype, and low risk and may not be a candidate for BCR-targeted therapies.
B细胞受体（BCR）信号传导对于正常和肿瘤性B细胞的存活至关重要，针对BCR信号通路的抑制剂已在B细胞淋巴瘤患者中显示出有前景的治疗效果。在本研究中，我们分析了25例无BCR表达的初发性弥漫性大B细胞淋巴瘤（DLBCL，BCR），以确定BCR/磷脂酰肌醇-3-激酶/AKT（BCR/PI3K/AKT）信号状态、临床病理特征以及导致BCR缺失的潜在原因。根据临床特征，15例（60%）DLBCL，BCR患者被归类为低风险组，18例（86%）实现完全缓解。在形态学和免疫表型上，DLBCL，BCR表现为中心母细胞性细胞学特征（21/25，84%）和生发中心B细胞样细胞起源（18/25，72%）。基于免疫组化结果，BCR复杂性中的其他成分保持完整。爱泼斯坦-巴尔病毒感染、B系转录因子（PAX5、Oct-2和Bob.1）缺乏以及癌基因重排似乎与BCR缺失无关。参与BCR/PI3K/AKT途径的信号蛋白（pSYK和pAKT）的活化形式在DLBCL，BCR组织中低水平表达。体外验证显示，在DLBCL，BCR细胞系中，BCR/PI3K/AKT途径对BCR刺激或抑制无反应。我们的研究结果表明，DLBCL，BCR的特征是BCR/PI3K/AKT途径沉默、生发中心表型和低风险，可能不是BCR靶向治疗的候选对象。
