T细胞淋巴母细胞淋巴瘤（T-LBL）是一种高度侵袭性的非霍奇金淋巴瘤，预后较差。 P21 激活激酶 (PAK) 是基于基因表达的分类器的一个组成部分，可以预测 T-LBL 的预后。然而，PAK 在 T-LBL 进展和生存中的作用仍知之甚少。在此，我们发现与人 T 淋巴细胞系相比，PAK1 在 T-LBL 细胞系（Jurkat、SUP-T1 和 CCRF-CEM）中的表达显着较高。此外，32 例复发 T-LBL 患者的 PAK2 mRNA 水平显着高于 37 例未复发的患者 (P = .012)。 PAK1 和 PAK2 高表达的 T-LBL 患者的中位 RFS 明显短于 PAK1 和 PAK2 低表达的患者（PAK1，P = .028；PAK2，P = .027；PAK1/2，P = .032）。 PAK 抑制剂 PF3758309 (PF) 和 FRAX597 可以通过阻断 G1/S 细胞周期相变来抑制 T-LBL 细胞的增殖。此外，PF可以增强体内外对阿霉素的化疗敏感性。从机制上来说，通过蛋白质印迹和RNA测序，我们发现PF可以抑制T-LBL细胞系中PAK1/2的磷酸化并下调cyclin D1、NF-κB和细胞粘附信号通路的表达。这些发现表明PAK可能与T-LBL复发有关，并进一步发现PAK抑制剂可以抑制多柔比星处理的T-LBL细胞的增殖并增强其化疗敏感性。总的来说，我们目前的研究强调了 T-LBL 治疗中抑制 PAK 的潜在治疗效果。版权所有 © 2023 作者。由威科健康公司代表中华医学会 (CMA) 和中国医学科学院血液学研究所发布

T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive non-Hodgkin lymphoma with a poor prognosis. P21-activated kinase (PAK) is a component of the gene expression-based classifier that can predict the prognosis of T-LBL. However, the role of PAK in T-LBL progression and survival remains poorly understood. Herein, we found that the expression of PAK1 was significantly higher in T-LBL cell lines (Jurkat, SUP-T1, and CCRF-CEM) compared to the human T-lymphoid cell line. Moreover, PAK2 mRNA level of 32 relapsed T-LBL patients was significantly higher than that of 37 cases without relapse (P = .012). T-LBL patients with high PAK1 and PAK2 expression had significantly shorter median RFS than those with low PAK1 and PAK2 expression (PAK1, P = .028; PAK2, P = .027; PAK1/2, P = .032). PAK inhibitors, PF3758309 (PF) and FRAX597, could suppress the proliferation of T-LBL cells by blocking the G1/S cell cycle phase transition. Besides, PF could enhance the chemosensitivity to doxorubicin in vitro and in vivo. Mechanistically, through western blotting and RNA sequencing, we identified that PF could inhibit the phosphorylation of PAK1/2 and downregulate the expression of cyclin D1, NF-κB and cell adhesion signaling pathways in T-LBL cell lines. These findings suggest that PAK might be associated with T-LBL recurrence and further found that PAK inhibitors could suppress proliferation and enhance chemosensitivity of T-LBL cells treated with doxorubicin. Collectively, our present study underscores the potential therapeutic effect of inhibiting PAK in T-LBL therapy.Copyright © 2023 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the Chinese Medical Association (CMA) and Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College (IHCAMS).