Diffuse Large B Cell Lymphoma Cell Line U-2946: Model for MCL1 Inhibitor Testing

Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma worldwide. We describe the establishment and molecular characteristics of the DLBCL cell line U-2946. This cell line was derived from a 52-year-old male with DLBCL. U-2946 cells carried the chromosomal translocation t(8;14) and strongly expressed MYC, but not the mature B-cell lymphoma associated oncogenes BCL2 and BCL6. Instead, U-2946 cells expressed the antiapoptotic BCL2 family member MCL1 which was highly amplified genomically (14n). MCL1 amplification is recurrent in DLBCL, especially in the activated B cell (ABC) variant. Results of microarray expression cluster analysis placed U-2946 together with ABC-, but apart from germinal center (GC)-type DLBCL cell lines. The 1q21.3 region including MCL1 was focally coamplified with a short region of 17p11.2 (also present at 14n). The MCL1 inhibitor A-1210477 triggered apoptosis in U-2946 (MCL1pos/BCL2neg) cells. In contrast to BCL2pos DLBCL cell lines, U-2946 did not respond to the BCL2 inhibitor ABT-263. In conclusion, the novel characteristics of cell line U-2946 renders it a unique model system to test the function of small molecule inhibitors, especially when constructing a panel of DLBCL cell lines expressing broad combinations of antiapoptotic BCL2-family members.弥漫性大B细胞淋巴瘤（Diffuse large B cell lymphoma, DLBCL）是全球范围内最常见的非霍奇金淋巴瘤亚型。本研究详细阐述了DLBCL细胞系U-2946的建立过程及其分子特征。该细胞系源自一名52岁的DLBCL男性患者。U-2946细胞携带有染色体易位t(8;14)，并强表达MYC基因，却不表达成熟B细胞淋巴瘤相关致癌基因BCL2与BCL6。与之不同的是，U-2946细胞表达抗凋亡BCL2家族成员MCL1，该基因在基因组中发生高水平扩增（14n）。MCL1基因扩增在DLBCL中频发出现，尤其多见于活化B细胞（activated B cell, ABC）亚型。基因芯片表达聚类分析结果显示，U-2946细胞系与ABC型DLBCL细胞系聚为一类，而与生发中心（germinal center, GC）型DLBCL细胞系相区分。包含MCL1的1q21.3区域与17p11.2的一段短区域发生局灶性共扩增，该区域同样呈现14n拷贝数异常。MCL1抑制剂A-1210477可诱导U-2946（MCL1阳性/BCL2阴性）细胞发生凋亡。与BCL2阳性的DLBCL细胞系不同，U-2946对BCL2抑制剂ABT-263无应答。综上，细胞系U-2946的独特全新特征使其成为极具价值的研究模型系统，可用于检测小分子抑制剂的功能；尤其在构建覆盖多种抗凋亡BCL2家族成员表达组合的DLBCL细胞系组合时，该细胞系的应用优势更为显著。