Dutta Rudra Prasad, Lee Heng-Huan, Leshchenko Violetta V, Shukla Ravi Prakash, Yan Fangfang, Liu Yang, Kaniskan H Ümit, Qiu Xing, Jin Jian, Alinari Lapo, Wang Michael L, Parekh Samir
Icahn School of Medicine at Mount Sinai, New York, New York, United States.
The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States.
Blood Adv. 2025 Aug 22. doi: 10.1182/bloodadvances.2025016801.
Mantle cell lymphoma (MCL) is an incurable subtype of B-cell non-Hodgkin lymphoma (NHL). Despite multiple approved Bruton tyrosine kinase inhibitors (BTKi), resistance to BTKi continues to pose a major clinical challenge. The transcription factor SOX11 is expressed in most MCL patients and is associated with poor outcomes. We have previously demonstrated SOX11-dependent BCR signaling in transgenic models of MCL. Here, we report that SOX11 drives BCR signaling by transcriptional activation of the PAX5-CD19 axis. The translational potential of these results is significant as scRNA-seq data show SOX11 is overexpressed in Ibrutinib-resistant patients as compared to Ibrutinib-sensitive patients. Treatment with the SOX11 DNA-binding inhibitor (SOX11i) significantly reduces the expression of PAX5, CD19, and components of BCR signaling in both Ibrutinib-sensitive and Ibrutinib-resistant cell lines. Importantly, SOX11i was able to demonstrate cytotoxicity in cells derived from Ibrutinib-resistant, Venetoclax (BCL2i) and CAR-T resistant PDX models in vitro. SOX11i treatment reduced the tumor growth in vivo in a MCL xenograft model without any significant toxicity. SOX11 inhibition offers significant potential for MCL patients, especially BTKi resistant patients, by targeting upstream resistance mechanisms.
套细胞淋巴瘤（MCL）是B细胞非霍奇金淋巴瘤（NHL）的一种无法治愈的亚型。尽管有多种已获批的布鲁顿酪氨酸激酶抑制剂（BTKi），但对BTKi的耐药性仍然是一个重大的临床挑战。转录因子SOX11在大多数MCL患者中表达，且与不良预后相关。我们之前在MCL转基因模型中证明了SOX11依赖性BCR信号传导。在此，我们报告SOX11通过PAX5-CD19轴的转录激活来驱动BCR信号传导。这些结果的转化潜力很大，因为单细胞RNA测序（scRNA-seq）数据显示，与对伊布替尼敏感的患者相比，SOX11在对伊布替尼耐药的患者中过度表达。用SOX11 DNA结合抑制剂（SOX11i）治疗可显著降低伊布替尼敏感和伊布替尼耐药细胞系中PAX5、CD19以及BCR信号传导成分的表达。重要的是，SOX11i能够在体外对源自伊布替尼耐药、维奈克拉（BCL2i）和CAR-T耐药的人源肿瘤异种移植（PDX）模型的细胞表现出细胞毒性。在MCL异种移植模型中，SOX11i治疗可在体内减少肿瘤生长，且无任何明显毒性。通过靶向上游耐药机制，抑制SOX11为MCL患者，尤其是对BTKi耐药的患者提供了巨大的潜力。
