Kady Nermin, Abdelrahman Suhaib, Rauf Ahmar M, Burgess Alyssa, Weiss Jonathan, Gunasekara Hirushi, Ramseier Neal, Maine Ira P, Zevallos-Morales Alejandro, Perez-Silos Vanessa, Wolfe Ashley, Hristov Alexandra C, Brown Noah A, Inamdar Kedar, Sverdlov Maria, Hu Ying S, Murga-Zamalloa Carlos, Wang Chenguang, Wilcox Ryan A
Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.
Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Blood. 2025 Feb 6;145(6):597-611. doi: 10.1182/blood.2024025484.
The transcription factor GATA-binding protein 3 (GATA-3) and the transcriptional program it regulates have emerged as oncogenic drivers across diverse T-cell lymphomas (TCLs), many of which are resistant to conventional chemotherapeutic agents and characterized by recurrent losses of key tumor suppressor genes, including TP53 and PTEN, both of which are clients of the nuclear export protein XPO1. Here, we demonstrated that XPO1 is highly expressed by malignant T cells expressing GATA-3 and by lymphoma-associated macrophages (LAMs) within their tumor microenvironment (TME). Using complementary genetically engineered mouse models, we demonstrated that TP53- and/or phosphate and tensin homolog (PTEN)-deficient TCLs, and LAMs within their TME, are sensitive to the selective exportin-1 (XPO1) antagonist selinexor. In an effort to identify TP53- and PTEN-independent mechanisms, we used complementary and orthogonal approaches to investigate the role of eIF4E and XPO1-dependent messenger RNA nuclear export in these TCLs. We identified a novel role for eIF4E/XPO1 in exporting GATA-3 and GATA-3-dependent transcripts from the nucleus in TCLs, and in the export of therapeutically relevant transcripts, including colony-stimulating factor-1 receptor, from LAMs. Therefore, XPO1 antagonism, by impairing oncogenic transcriptional programs in TCLs and depleting LAMs from their TME, is a novel approach to target 2 independent dependencies in a group of therapeutically challenging TCLs.
转录因子GATA结合蛋白3（GATA-3）及其调控的转录程序已成为多种T细胞淋巴瘤（TCL）的致癌驱动因素，其中许多对传统化疗药物耐药，且其特征是关键肿瘤抑制基因（包括TP53和PTEN）经常缺失，这两个基因都是核输出蛋白XPO1的底物。在此，我们证明XPO1在表达GATA-3的恶性T细胞及其肿瘤微环境（TME）中的淋巴瘤相关巨噬细胞（LAM）中高表达。使用互补的基因工程小鼠模型，我们证明TP53和/或磷酸酶和张力蛋白同源物（PTEN）缺陷的TCL及其TME中的LAM对选择性核输出蛋白1（XPO1）拮抗剂塞利尼索敏感。为了确定不依赖TP53和PTEN的机制，我们使用互补和正交方法研究真核翻译起始因子4E（eIF4E）和XPO1依赖的信使核糖核酸核输出在这些TCL中的作用。我们发现eIF4E/XPO1在将GATA-3和GATA-3依赖的转录本从TCL细胞核输出以及从LAM输出包括集落刺激因子1受体在内的治疗相关转录本方面具有新作用。因此，通过损害TCL中的致癌转录程序并从其TME中清除LAM，XPO1拮抗作用是针对一组治疗上具有挑战性的TCL中2种独立依赖性的新方法。
