Glaser Selina, Wagener Rabea, Harkins Shannon K, Voena Claudia, Bens Susanne, Klapper Wolfram, Laurent Camille, Mathas Stephan, Ren Meiqi, Sander Sandrine, Schnaudt-Mastrangelo Charlotte, Wößmann Wilhelm, Xerri Luc, Ammerpohl Ole, Zelenetz Andrew D, Louissaint Abner, Chiarle Roberto, Siebert Reiner
Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.
Institute of Human Genetics, Christian-Albrechts-University Kiel, Kiel, Germany.
Genes Chromosomes Cancer. 2025 Jul;64(7):e70060. doi: 10.1002/gcc.70060.
Structural genomic variants leading to anaplastic lymphoma kinase (ALK) gene fusions and aberrant expression of the ALK tyrosine kinase are the hallmark of subtypes of T- and B-lineage neoplasms, namely ALK-positive anaplastic large lymphoma (ALCL) and ALK-positive large B-cell lymphoma (LBCL). The latter is a rare aggressive lymphoma, which has been initially identified as a variant of diffuse LBCL (DLBCL) with plasmablastic features. Here, we performed comparative DNA methylation profiling of human and murine ALK-positive B-cell neoplasms. Array-based DNA methylation data from ALK-positive LBCL samples of eight patients were compared to that of DLBCL (n = 75), multiple myeloma (MM, n = 24), ALK-positive ALCL (n = 12) and normal B-cell populations (n = 93). ALK-positive LBCLs share a distinct DNA methylation signature similar to that of MM, characterized by lower global DNA methylation levels compared to DLBCLs and normal B-cell populations. DNA methylation alterations in ALK-positive LBCL were predominantly located in heterochromatic and polycomb-repressed regions. The epigenetic age and relative proliferative history of ALK-positive LBCL were intermediate between MM and DLBCL. B-cell neoplasms in NPM::ALK transgenic mice showed a similar hypomethylated signature when compared to normal murine B cells. Cross-species comparison indicated conservation of chromatin states and pathways affected by hypomethylation. Together, the findings suggest that in line with their phenotypical appearance human and murine ALK-positive B-cell lymphomas share an epigenetic profile more closely resembling that of plasma cell neoplasias than that of DLBCLs.
导致间变性淋巴瘤激酶（ALK）基因融合以及ALK酪氨酸激酶异常表达的结构基因组变异是T和B淋巴细胞肿瘤亚型的标志，即ALK阳性间变性大细胞淋巴瘤（ALCL）和ALK阳性大B细胞淋巴瘤（LBCL）。后者是一种罕见的侵袭性淋巴瘤，最初被鉴定为具有浆母细胞特征的弥漫性大B细胞淋巴瘤（DLBCL）的变异型。在此，我们对人和小鼠ALK阳性B细胞肿瘤进行了比较DNA甲基化分析。将8例患者的ALK阳性LBCL样本基于芯片的DNA甲基化数据与DLBCL（n = 75）、多发性骨髓瘤（MM，n = 24）、ALK阳性ALCL（n = 12）和正常B细胞群体（n = 93）的数据进行比较。ALK阳性LBCL具有与MM相似的独特DNA甲基化特征，其特点是与DLBCL和正常B细胞群体相比，整体DNA甲基化水平较低。ALK阳性LBCL中的DNA甲基化改变主要位于异染色质和多梳蛋白抑制区域。ALK阳性LBCL的表观遗传年龄和相对增殖史介于MM和DLBCL之间。与正常小鼠B细胞相比，NPM::ALK转基因小鼠中的B细胞肿瘤表现出相似的低甲基化特征。跨物种比较表明受低甲基化影响的染色质状态和途径具有保守性。总之，这些发现表明，与它们的表型外观一致，人和小鼠ALK阳性B细胞淋巴瘤共享一种表观遗传学特征，与浆细胞肿瘤的表观遗传学特征比与DLBCL的表观遗传学特征更为相似。
