Nagel Stefan, Pommerenke Claudia, Meyer Corinna, Kaufmann Maren, MacLeod Roderick A F
Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Inhoffenstr. 7B, 38124 Braunschweig, Germany.
Biomedicines. 2023 Jun 19;11(6):1758. doi: 10.3390/biomedicines11061758.
, and are major oncogenes in B-cell lymphoma. Their aberrant activation frequently occurs via chromosomal translocations which juxtapose light or heavy chain immunoglobulin (IG) genes to and or fuse diverse partner genes with . So-called double-hit lymphomas usually carry and rearrangements, while triple-hit lymphomas additionally bear -fusions. All these translocations are of diagnostic relevance and usually denote poor prognosis. Here, we genomically characterized classic follicular lymphoma (FL) cell line SC-1, thereby identifying t(14;18)(q32;q21) juxtaposing and , t(8;14)(q24;q32) juxtaposing and , and t(3;3)(q25;q27) fusing to . In addition, we found that SC-1 carries a novel chromosomal rearrangement, t(14;17)(q32;q21), which, though present at establishment, has remained unreported until now. We further show that t(14;17)(q32;q21) juxtaposes with the HOXB gene cluster at 17q21 and affect the oncogenic activation of both homeobox gene and neighboring micro-RNA gene . Moreover, we detected aberrant overexpression of in subsets of Burkitt lymphoma, FL, and multiple myeloma patients, confirming the clinical relevance of its deregulation. In SC-1, activation was additionally supported by co-expression of hematopoietic stem cell factor ZNF521, indicating an aberrant impact in cell differentiation. Functional investigations showed that HOXB5 represses the apoptotic driver and promotes survival in the presence of etoposide, and that inhibits BCL6 and may thus play an oncogenic role in later stages of lymphomagenesis. Collectively, we characterize triple-hit B-cell line SC-1 and identify the aberrant expression of and , both novel oncogenes in B-cell lymphoma.
、 和 是B细胞淋巴瘤中的主要致癌基因。它们的异常激活经常通过染色体易位发生，这种易位使轻链或重链免疫球蛋白（IG）基因与 和 并列，或者使不同的伙伴基因与 融合。所谓的双打击淋巴瘤通常携带 和 重排，而三打击淋巴瘤还额外存在 -融合。所有这些易位都具有诊断相关性，通常预示着预后不良。在这里，我们对经典滤泡性淋巴瘤（FL）细胞系SC-1进行了基因组特征分析，从而鉴定出将 和 并列的t(14;18)(q32;q21)、将 和 并列的t(8;14)(q24;q32)以及将 与 融合的t(3;3)(q25;q27)。此外，我们发现SC-1携带一种新的染色体重排t(14;17)(q32;q21)，尽管它在细胞系建立时就已存在，但直到现在仍未被报道。我们进一步表明，t(14;17)(q32;q21)使 与17q21处的HOXB基因簇并列，并影响同源盒基因 和邻近的微小RNA基因 的致癌激活。此外，我们在伯基特淋巴瘤、FL和多发性骨髓瘤患者的亚组中检测到 的异常过表达，证实了其失调的临床相关性。在SC-1中，造血干细胞因子ZNF521的共表达额外支持了 的激活，表明其对细胞分化有异常影响。功能研究表明，HOXB5抑制凋亡驱动因子 并在依托泊苷存在的情况下促进存活，并且 抑制BCL6，因此可能在淋巴瘤发生的后期发挥致癌作用。总体而言，我们对三打击B细胞系SC-1进行了特征分析，并鉴定出 和 这两个B细胞淋巴瘤中的新致癌基因的异常表达。
