Mantle cell lymphoma (MCL) is considered one of the most aggressive B-cell lymphoid neoplasms. The transcription factor SOX11 is aberrantly expressed in conventional aggressive MCL, while it is not or weakly expressed in the leukemic non-nodal MCL subtype with a predominantly indolent clinical evolution. SOX11 is a key driver of MCL through the regulation of several oncogenic mechanisms, suggesting that it may be interacting with different protein complexes to exert its multiple actions. Using proteomic strategies, we characterized the SOX11-interactome and validated its physical interaction with SMARCA4, the catalytic subunit of the SWI/SNF chromatin-remodeling complex. SMARCA4 expression is directly regulated by SOX11, and its upregulation significantly associates with worse outcomes of patients. Integration of global DNA-binding and transcriptomic profiles revealed that SOX11 and SMARCA4 share binding sites enriched in open chromatin and active promoters and regulate common key oncogenic pathways crucial for MCL progression and aggressiveness. The SMARCA4-specific PROTAC-degrader AU-15330 significantly reduced SOX11 binding to specific regulatory regions and diminished the activation of BCR-, NIK-, and BCL2-signaling pathways. Moreover, SMARCA4 degradation significantly reduced proliferation and induced apoptosis of SOX11-positive MCL cells, highlighting AU-15330 as a promising therapeutic approach for patients who may relapse from current target therapies in MCL.
套细胞淋巴瘤（MCL）被认为是最具侵袭性的B细胞淋巴肿瘤之一。转录因子SOX11在常规侵袭性MCL中异常表达，而在以惰性临床进展为主的白血病性非结节性MCL亚型中不表达或弱表达。SOX11通过调节多种致癌机制，是MCL的关键驱动因子，这表明它可能与不同的蛋白质复合物相互作用以发挥其多重作用。利用蛋白质组学策略，我们表征了SOX11的相互作用组，并验证了其与SWI/SNF染色质重塑复合物的催化亚基SMARCA4的物理相互作用。SMARCA4的表达受SOX11直接调控，其上调与患者较差的预后显著相关。整合全局DNA结合和转录组学分析显示，SOX11和SMARCA4共享富含开放染色质和活性启动子的结合位点，并调节对MCL进展和侵袭性至关重要的共同关键致癌通路。SMARCA4特异性的PROTAC降解剂AU-15330显著降低了SOX11与特定调控区域的结合，并减弱了BCR-、NIK-和BCL2信号通路的激活。此外，SMARCA4的降解显著减少了SOX11阳性MCL细胞的增殖并诱导了细胞凋亡，这突显了AU-15330作为一种有前景的治疗方法，适用于可能从当前MCL靶向治疗中复发的患者。
The SOX11:SMARCA4 complex is a driver of oncogenic transcriptional programs in mantle cell lymphoma
肿瘤(癌症)患者之家