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Abstract：
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.
摘要：
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，预后不良。P21激活激酶（PAK）是基于基因表达的分类器的组成部分，可以预测T-LBL的预后。然而,PAK在T-LBL进展和生存中的作用尚不清楚.在这里，我们发现PAK1在T-LBL细胞系中的表达明显更高(Jurkat，SUP-T1和CCRF-CEM）与人T淋巴样细胞系相比。此外，32例复发T-LBL患者的PAK2mRNA水平明显高于37例未复发患者（P=0.012）。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细胞周期的相变来抑制T-LBL细胞的增殖。此外,PF可以在体外和体内增强对阿霉素的化学敏感性。机械上,通过蛋白质印迹和RNA测序，我们发现PF可以抑制PAK1/2的磷酸化，并下调T-LBL细胞系中细胞周期蛋白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细胞的增殖并增强化学敏感性。总的来说，本研究强调了T-LBL治疗中抑制PAK的潜在治疗作用.
