抑制PAK1对MPLW515L小鼠骨髓增生性肿瘤模型产生改善作用，通过调节巨核细胞的分化和存活。
Inhibition of PAK1 generates an ameliorative effect on MPLW515L mouse model of myeloproliferative neoplasms by regulating the differentiation and survival of the megakaryocytes.
发表日期：2023 Sep 21
作者：
Chunling Fu, Xueting Hu, Shujin Wang, Xiangru Yu, Qigang Zhang, Liwei Zhang, Kunming Qi, Zhenyu Li, Kailin Xu
来源：
Experimental Hematology & Oncology
摘要：
在脾脏或骨髓中，大部分血小板生成素受体 (MPL) 突变导致异常的巨核细胞扩增，进而引发纤维化的进展。早先有研究报道表明，p21（RAC1）活化激酶1 (PAK1) 参与了巨核母细胞增殖和分化，该研究发现，目前的研究中，患有骨髓增殖性肿瘤 (MPN) 和 MPLW515L 突变基因的小鼠 MPN 细胞中，PAK1 的磷酸化增加；然而，在 MPN 细胞中，过度活化的 PAK1 的功能尚不清楚。我们发现抑制 PAK1 在体外会导致 MPLW515L 突变细胞的生物学行为发生显著变化，包括生长停滞或克隆性减少以及多倍体 DNA 和细胞凋亡增加，这是由于上调了剪切的半胱天冬酶 3 所致。在体内，PAK1 抑制剂治疗导致 6133/MPLW515L 移植小鼠出现缓慢的白细胞增多和红细胞比容 (HCT) 升高，同时肝脾肿大减轻，出现肿瘤细胞浸润减少和生存时间延长。进一步删除 PAK1 在疾病开始初期维持相对正常的 HCT 和血小板计数，但无法完全减轻 MPLW515L 突变小鼠的脾肿大。值得注意的是，PAK1 基因敲除减弱了脾结构的破坏，在骨髓中减少了巨核细胞负担。这些结果提示抑制 PAK1 可能是一种治疗 MPLW515L 突变 MPN 的相当方法，通过干预巨核细胞。© 2023 Elsevier Ltd. 保留所有权利。
Most thrombopoietin receptor (MPL) mutations result in abnormal megakaryocyte expansion in the spleen or bone marrow (BM), leading to progressive fibrosis. It has been reported that p21 (RAC1)-activated kinase 1 (PAK1) participates in the proliferation and differentiation of megakaryoblast, PAK1 phosphorylation was found to be increased in patients with myeloproliferative neoplasm (MPNs) and murine MPN cells with the MPLW515L mutant gene in the present study; however, the function of the over activated PAK1 in MPN cells remains unclear. We found that inhibition of PAK1 caused significant changes in the biological behaviors of MPLW515L mutant cells in vitro, including arrested growth or reduced clonality as well as increased polyploid DNA and cells apoptosis due to upregulated cleaved caspase 3. In vivo, PAK1 inhibitor treatment caused a slow elevation of leukocytosis and hematocrit (HCT) and reduction in hepatosplenomegaly in 6133/MPLW515L transplanted mice, along with reduced tumor cell infiltration and prolonged survival. Further deletion of PAK1 sustained a relatively normal HCT and platelet count at the beginning of disease but did not completely alleviate the splenomegaly of MPLW515L mutant mice. Notably, PAK1 knockout attenuated the destruction of splenic structure, and reduced the megakaryocyte burden within the BM. These results suggest that the inhibition of PAK1 may be a considerable method treating MPLW515L mutant MPN by intervening megakaryocytes.Copyright © 2023 Elsevier Ltd. All rights reserved.