Multiple myeloma (MM) is a heterogeneous disease characterized by significant genomic instability. Recently, a causal role for the AID/APOBEC deaminases in inducing somatic mutations in myeloma has been reported. We have identified APOBEC/AID as a prominent mutational signature at diagnosis with further increase at relapse in MM. In this study, we identified upregulation of several members of APOBEC3 family (A3A, A3B, A3C, and A3G) with A3G, as one of the most expressed APOBECs. We investigated the role of APOBEC3G in MM and observed that A3G expression and APOBEC deaminase activity is elevated in myeloma cell lines and patient samples. Loss-of and gain-of function studies demonstrated that APOBEC3G significantly contributes to increase in DNA damage (abasic sites and DNA breaks) in MM cells. Evaluation of the impact on genome stability, using SNP arrays and whole genome sequencing, indicated that elevated APOBEC3G contributes to ongoing acquisition of both the copy number and mutational changes in MM cells over time. Elevated APOBEC3G also contributed to increased homologous recombination activity, a mechanism that can utilize increased DNA breaks to mediate genomic rearrangements in cancer cells. These data identify APOBEC3G as a novel gene impacting genomic evolution and underlying mechanisms in MM.

多发性骨髓瘤（MM）是一种异质性疾病，其特征是基因组显着不稳定。最近，AID/APOBEC 脱氨酶在诱导骨髓瘤体细胞突变中的因果作用已被报道。我们已将 APOBEC/AID 确定为诊断时的一个显着突变特征，并且在 MM 复发时进一步增加。在这项研究中，我们确定了 APOBEC3 家族的几个成员（A3A、A3B、A3C 和 A3G）的上调，其中 A3G 是表达最多的 APOBEC 之一。我们研究了 APOBEC3G 在 MM 中的作用，并观察到骨髓瘤细胞系和患者样本中 A3G 表达和 APOBEC 脱氨酶活性升高。功能丧失和获得的研究表明，APOBEC3G 显着导致 MM 细胞中 DNA 损伤（脱碱基位点和 DNA 断裂）的增加。使用 SNP 阵列和全基因组测序评估对基因组稳定性的影响表明，升高的 APOBEC3G 有助于随着时间的推移持续获取 MM 细胞中的拷贝数和突变变化。 APOBEC3G 升高还有助于增加同源重组活性，这是一种可以利用增加的 DNA 断裂来介导癌细胞基因组重排的机制。这些数据将 APOBEC3G 确定为影响 MM 基因组进化和潜在机制的新基因。