Multiple myeloma (MM) remains an intractable hematological malignancy, despite recent advances in anti-MM drugs. Here, we show that role of PDZ binding kinase (PBK) in MM tumor growth. We identified that interleukin-6 (IL-6) readily increases PBK expression. Kaplan–Meier analysis showed that the MM patients with higher expression of PBK have a significant shorter survival time compared with those with moderate/lower expression of PBK. Knockout of PBK dramatically suppressed in vivo tumor growth in MM cells, while genome editing of PBK changing from asparagine to serine substitution (rs3779620) slightly suppresses the tumor formation. Mechanistically, loss of PBK increased the number of apoptotic cells with concomitant decrease in the phosphorylation level of Stat3 as well as caspase activities. A novel PBK inhibitor OTS514 significantly decreased KMS-11-derived tumor growth. These findings highlight the novel oncogenic role of PBK in tumor growth of myeloma, and it might be a novel therapeutic target for the treatment of patients with MM.

中文翻译：

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新型白细胞介素 6 诱导基因 PDZ 结合激酶促进多发性骨髓瘤细胞的肿瘤生长。

尽管最近在抗 MM 药物方面取得了进展，但多发性骨髓瘤 (MM) 仍然是一种顽固的血液系统恶性肿瘤。在这里，我们展示了 PDZ 结合激酶 (PBK) 在 MM 肿瘤生长中的作用。我们发现白细胞介素 6 (IL-6) 很容易增加 PBK 表达。Kaplan-Meier 分析表明，与 PBK 中/低表达的 MM 患者相比，PBK 高表达的 MM 患者的生存时间显着缩短。PBK 的敲除显着抑制了MM 细胞的体内肿瘤生长，而PBK 的基因组编辑从天冬酰胺变为丝氨酸取代 (rs3779620) 略微抑制了肿瘤的形成。从机制上讲，PBK 的损失增加凋亡细胞的数量，同时降低 Stat3 的磷酸化水平以及半胱天冬酶活性。一种新型 PBK 抑制剂 OTS514 显着降低了 KMS-11 衍生的肿瘤生长。这些发现突出了 PBK 在骨髓瘤肿瘤生长中的新致癌作用，它可能是治疗 MM 患者的新治疗靶点。