Department of Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Division of Hematology, Department of Internal of Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Cancer Res Commun. 2024 Feb 9;4(2):349-364. doi: 10.1158/2767-9764.CRC-23-0215.
CD26 is ubiquitously and intensely expressed in osteoclasts in patients with multiple myeloma, whereas its expression in plasma cells of patients with multiple myeloma is heterogeneous because of its cellular diversity, immune escape, and disease progression. Decreased expression levels of CD26 in myeloma cells constitute one of the mechanisms underlying resistance to humanized anti-CD26 mAb therapy in multiple myeloma. In the current study, we show that histone deacetylase inhibition (HDACi) with broad or class-specific inhibitors involves the induction of CD26 expression on CD26neg myeloma cells both transcriptionally and translationally. Furthermore, dipeptidyl peptidase Ⅳ (DPPⅣ) enzymatic activity was concomitantly enhanced in myeloma cells. Combined treatment with HDACi plus CD26mAb synergistically facilitated lysis of CD26neg myeloma cells not only by antibody-dependent cellular cytotoxicity but also by the direct effects of mAb. Of note, its combination readily augmented lysis of CD26neg cell populations, refractory to CD26mAb or HDACi alone. Chromatin immunoprecipitation assay revealed that HDACi increased acetylation of histone 3 lysine 27 at the CD26 promoter of myeloma cells. Moreover, in the absence of HDACi, c-Myc was attached to the CD26 promoter via Sp1 on the proximal G-C box of myeloma cells, whereas, in the presence of HDACi, c-Myc was detached from Sp1 with increased acetylation of c-Myc on the promoter, leading to activation of the CD26 promoter and initiation of transcription in myeloma cells. Collectively, these results confirm that HDACi plays crucial roles not only through its anti-myeloma activity but by sensitizing CD26neg myeloma cells to CD26mAb via c-Myc/Sp1-mediated CD26 induction, thereby augmenting its cytotoxicity.
There is a desire to induce and sustain CD26 expression on multiple myeloma cells to elicit superior anti-myeloma response by humanized anti-CD26 mAb therapy. HDACi upregulates the expression levels of CD26 on myeloma cells via the increased acetylation of c-MycK323 on the CD26 promoter, leading to initiation of CD26 transcription, thereby synergistically augments the efficacy of CD26mAb against CD26neg myeloma cells.
在多发性骨髓瘤患者中，CD26 在破骨细胞中广泛且强烈表达，而由于其细胞多样性、免疫逃避和疾病进展，多发性骨髓瘤患者浆细胞中的 CD26 表达存在异质性。骨髓瘤细胞中 CD26 表达水平的降低是导致抗人源化抗 CD26 mAb 治疗多发性骨髓瘤产生耐药的机制之一。在本研究中，我们表明，广谱或特定类别组蛋白去乙酰化酶抑制剂 (HDACi) 通过转录和翻译诱导 CD26neg 骨髓瘤细胞表达 CD26。此外，二肽基肽酶 4（DPPIV）酶活性也同时在骨髓瘤细胞中增强。HDACi 联合 CD26mAb 治疗可协同促进 CD26neg 骨髓瘤细胞的裂解，不仅通过抗体依赖的细胞毒性，还通过 mAb 的直接作用。值得注意的是，它的组合很容易增强对 CD26mAb 或 HDACi 单独治疗有抗性的 CD26neg 细胞群的裂解。染色质免疫沉淀分析表明，HDACi 增加了骨髓瘤细胞中 CD26 启动子处组蛋白 3 赖氨酸 27 的乙酰化。此外，在没有 HDACi 的情况下，c-Myc 通过骨髓瘤细胞近端 G-C 盒上的 Sp1 附着在 CD26 启动子上，而在存在 HDACi 的情况下，c-Myc 与 Sp1 脱离，c-Myc 在启动子上的乙酰化增加，导致 CD26 启动子激活和骨髓瘤细胞中转录起始。总的来说，这些结果证实，HDACi 通过其抗骨髓瘤活性以及通过 c-Myc/Sp1 介导的 CD26 诱导使 CD26neg 骨髓瘤细胞对 CD26mAb 敏感来发挥至关重要的作用，从而增强其细胞毒性。
人们渴望诱导和维持多发性骨髓瘤细胞上的 CD26 表达，通过人源化抗 CD26 mAb 治疗来引发更强的抗骨髓瘤反应。HDACi 通过增加 CD26 启动子上 c-MycK323 的乙酰化来上调骨髓瘤细胞上 CD26 的表达水平，导致 CD26 转录的起始，从而协同增强 CD26mAb 对 CD26neg 骨髓瘤细胞的疗效。
