Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China.
Key Laboratory of Hematology of Nanjing Medical University, Nanjing, 210029, China.
Clin Exp Med. 2023 Oct;23(6):2651-2662. doi: 10.1007/s10238-023-01003-6. Epub 2023 Feb 4.
Chronic lymphocytic leukemia (CLL) is a subtype of B-cell malignancy with high heterogeneity. XPO1 is highly expressed in many hematological malignancies, which predicts poor prognosis. In the study, we aimed to explore the prognostic role of XPO1 and the therapeutic effect of Selinexor, a selective inhibitor of nuclear export, which targets XPO1. We collected 200 CLL samples in our center to confirm XPO1 mRNA expression and analyzed the correlation between XPO1 expression and prognosis. Then, we decreased XPO1 expression with Selinexor to explore the effect of proliferation inhibition, cell cycle arrest, and apoptosis in CLL cell lines. RNA-Seq was performed to explore potential mechanisms. We analyzed XPO1 expression in a cohort of 150 treatment naive patients and another cohort of 50 relapsed and refractory (R/R) patients and found that XPO1 expression was upregulated in 76% of CLL patients compared with healthy donors. Survival analysis suggested that patients with increased XPO1 expression had inferior treatment-free survival (P = 0.022) and overall survival (P = 0.032). The inhibitor of XPO1, Selinexor, induced apoptosis in primary CLL cells. We showed the effects of Selinexor on proliferation inhibition, cell cycle arrest, and apoptosis in CLL cell lines with JVM3, MEC1, and ibrutinib-resistant (MR) cells via nuclear retention of cargo proteins of IκBα, p65, p50, and FOXO3a. Moreover, downregulation of the NF-κB and FOXO pathways was a common feature of the three CLL cell lines responding to Selinexor, indicating the potential application of XPO1 inhibitor even in the high-risk CLL cells. We identified XPO1 as an unfavorable prognostic factor for CLL patients and provided a rationale for further investigation of the clinically XPO1 targeted therapeutic strategy against CLL.
慢性淋巴细胞白血病（CLL）是一种具有高度异质性的 B 细胞恶性肿瘤。XPO1 在许多血液恶性肿瘤中高度表达，预示着预后不良。在这项研究中，我们旨在探索 XPO1 的预后作用以及 Selinexor（一种靶向 XPO1 的核输出选择性抑制剂）的治疗效果。我们在中心收集了 200 例 CLL 样本，以确认 XPO1 mRNA 表达，并分析 XPO1 表达与预后的相关性。然后，我们使用 Selinexor 降低 XPO1 表达，以探索其对 CLL 细胞系增殖抑制、细胞周期停滞和凋亡的影响。进行 RNA-Seq 以探索潜在机制。我们分析了 150 例初治患者和 50 例复发/难治（R/R）患者队列中的 XPO1 表达，发现与健康供体相比，76%的 CLL 患者 XPO1 表达上调。生存分析表明，XPO1 表达增加的患者无治疗缓解期（P=0.022）和总生存期（P=0.032）更差。XPO1 抑制剂 Selinexor 诱导原代 CLL 细胞凋亡。我们通过核内保留 IκBα、p65、p50 和 FOXO3a 的货物蛋白，显示 Selinexor 在 JVM3、MEC1 和 ibrutinib 耐药（MR）细胞中对增殖抑制、细胞周期停滞和凋亡的影响。此外，下调 NF-κB 和 FOXO 通路是三种 CLL 细胞系对 Selinexor 反应的共同特征，表明即使在高危 CLL 细胞中，XPO1 抑制剂也具有潜在的应用价值。我们将 XPO1 鉴定为 CLL 患者不良预后的因素，并为进一步研究针对 CLL 的临床 XPO1 靶向治疗策略提供了依据。
