Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is driven by aberrant activation of the B-cell receptor (BCR) and the TLR/MyD88 signaling pathways. The heat-shock protein HSP110 is a candidate for their regulation as it stabilizes MyD88. However, its role in overall BCR signaling remains unknown. Here, we used first-in-class HSP110 inhibitors to address this question. HSP110 inhibitors decreased the survival of several ABC-DLBCL cell lines in vitro and in vivo, and reduced the phosphorylation of BCR signaling kinases, including BTK and SYK. We identified an interaction between HSP110 and SYK and demonstrated that HSP110 promotes SYK phosphorylation. Finally, the combination of the HSP110 inhibitor with the PI3K inhibitor copanlisib decreases SYK/BTK and AKT phosphorylation synergistically, leading to suppression of tumor growth in cell line xenografts and strong reduction in patient-derived xenografts. In conclusion, by regulating the BCR/TLR signaling pathway, HSP110 inhibitors are potential drug candidates for ABC-DLBCL patients.

活化的 B 细胞样弥漫性大 B 细胞淋巴瘤 （ABC-DLBCL） 是由 B 细胞受体 （BCR） 和 TLR/MyD88 信号通路的异常激活驱动的。热休克蛋白 HSP110 是其调节的候选者，因为它稳定 MyD88。然而，它在整体 BCR 信号转导中的作用仍然未知。在这里，我们使用了一流的 HSP110 抑制剂来解决这个问题。HSP110 抑制剂降低了几种 ABC-DLBCL 细胞系在体外和体内的存活率，并降低了 BCR 信号激酶（包括 BTK 和 SYK）的磷酸化。我们确定了 HSP110 和 SYK 之间的相互作用，并证明 HSP110 促进 SYK 磷酸化。最后，HSP110 抑制剂与 PI3K 抑制剂 copanlisib 的组合协同降低 SYK/BTK 和 AKT 磷酸化，导致抑制细胞系异种移植物中的肿瘤生长并强烈减少患者来源的异种移植物。总之，通过调节 BCR/TLR 信号通路，HSP110 抑制剂是 ABC-DLBCL 患者的潜在候选药物。