You Dewen, Xin Junping, Volk Andrew, Wei Wei, Schmidt Rachel, Scurti Gina, Nand Sucha, Breuer Eun-Kyoung, Kuo Paul C, Breslin Peter, Kini Ameet R, Nishimura Michael I, Zeleznik-Le Nancy J, Zhang Jiwang
Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA.
Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA.
Cell Rep. 2015 Mar 31;10(12):2055-68. doi: 10.1016/j.celrep.2015.02.056. Epub 2015 Mar 19.
Mutations and inactivation of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) are observed in 15%-25% of cases of human T cell acute lymphoblastic leukemia (T-ALL). Pten deletion induces myeloproliferative disorders (MPDs), acute myeloid leukemia (AML), and/or T-ALL in mice. Previous studies attributed Pten-loss-related hematopoietic defects and leukemogenesis to excessive activation of phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling. Although inhibition of this signal dramatically suppresses the growth of PTEN-null T-ALL cells in vitro, treatment with inhibitors of this pathway does not cause a complete remission in vivo. Here, we report that focal adhesion kinase (Fak), a protein substrate of Pten, also contributes to T-ALL development in Pten-null mice. Inactivation of the FAK signaling pathway by either genetic or pharmacologic methods significantly sensitizes both murine and human PTEN-null T-ALL cells to PI3K/AKT/mTOR inhibition when cultured in vitro on feeder layer cells or a matrix and in vivo.
在15%-25%的人类T细胞急性淋巴细胞白血病（T-ALL）病例中，可观察到第10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）发生突变和失活。Pten缺失会在小鼠中诱发骨髓增殖性疾病（MPD）、急性髓系白血病（AML）和/或T-ALL。先前的研究将Pten缺失相关的造血缺陷和白血病发生归因于磷脂酰肌醇3激酶（PI3K）/AKT/mTOR信号的过度激活。尽管抑制该信号在体外可显著抑制PTEN缺失的T-ALL细胞的生长，但用该信号通路的抑制剂进行治疗在体内并不能导致完全缓解。在此，我们报告粘着斑激酶（Fak）作为Pten的一种蛋白质底物，也在Pten缺失的小鼠的T-ALL发展中发挥作用。当在饲养层细胞或基质上体外培养以及在体内培养时，通过遗传或药理学方法使FAK信号通路失活可显著增强小鼠和人类PTEN缺失的T-ALL细胞对PI3K/AKT/mTOR抑制的敏感性。
