Tahara Kenichi, Takizawa Makiko, Yamane Arito, Osaki Yohei, Ishizaki Takuma, Mitsui Takeki, Yokohama Akihiko, Saitoh Takayuki, Tsukamoto Norifumi, Matsumoto Morio, Murakami Hirokazu, Nojima Yoshihisa, Handa Hiroshi
Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Gunma, Japan.
Division of Blood Transfusion Service, Gunma University Hospital, Gunma, Japan.
Cancer Sci. 2017 Aug;108(8):1556-1564. doi: 10.1111/cas.13283. Epub 2017 Jun 25.
B-cell lymphoma 6 (BCL6) attenuates DNA damage response (DDR) through gene repression and facilitates tolerance to genomic instability during immunoglobulin affinity maturation in germinal center (GC) B cells. Although BCL6 expression is repressed through normal differentiation of GC B cells into plasma cells, a recent study showed the ectopic expression of BCL6 in primary multiple myeloma (MM) cells. However, the functional roles of BCL6 in MM cells are largely unknown. Here, we report that overexpression of BCL6 in a MM cell line, KMS12PE, induced transcriptional repression of ataxia telangiectasia mutated (ATM), a DDR signaling kinase, which was associated with a reduction in γH2AX formation after DNA damage. In contrast, transcription of known targets of BCL6 in GC B cells was not affected, suggesting a cell type-specific function of BCL6. To further investigate the effects of BCL6 overexpression on the MM cell line, we undertook mRNA sequence analysis and found an upregulation in the genomic mutator activation-induced cytidine deaminase (AID) with alteration in the gene expression profile, which is suggestive of de-differentiation from plasma cells. Moreover, interleukin-6 exposure to KMS12PE led to upregulation of BCL6 and AID, downregulation of ATM, and attenuation of DDR, which were consistent with the effects of BCL6 overexpression in this MM cell line. Taken together, these results indicated that overexpression of BCL6 alters gene expression profile and confers decreased DDR in MM cells. This phenotypic change could be reproduced by interleukin-6 stimulation, suggesting an important role of external stimuli in inducing genomic instability, which is a hallmark of MM cells.
B细胞淋巴瘤6（BCL6）通过基因抑制减弱DNA损伤反应（DDR），并在生发中心（GC）B细胞免疫球蛋白亲和力成熟过程中促进对基因组不稳定的耐受性。尽管BCL6的表达在GC B细胞向浆细胞的正常分化过程中受到抑制，但最近的一项研究显示BCL6在原发性多发性骨髓瘤（MM）细胞中异位表达。然而，BCL6在MM细胞中的功能作用在很大程度上尚不清楚。在此，我们报告在MM细胞系KMS12PE中过表达BCL6会诱导共济失调毛细血管扩张突变（ATM）的转录抑制，ATM是一种DDR信号激酶，这与DNA损伤后γH2AX形成的减少有关。相反，GC B细胞中BCL6已知靶点的转录不受影响，这表明BCL6具有细胞类型特异性功能。为了进一步研究BCL6过表达对MM细胞系的影响，我们进行了mRNA序列分析，发现基因组突变体激活诱导的胞苷脱氨酶（AID）上调，基因表达谱发生改变，这提示从浆细胞去分化。此外，用白细胞介素-6处理KMS12PE会导致BCL6和AID上调、ATM下调以及DDR减弱，这与BCL6在该MM细胞系中过表达的作用一致。综上所述，这些结果表明BCL6过表达会改变MM细胞的基因表达谱并降低DDR。这种表型变化可通过白细胞介素-6刺激重现，表明外部刺激在诱导基因组不稳定中起重要作用，而基因组不稳定是MM细胞的一个标志。
