Shao Jingchen, Li Susann, Palmqvist Lars, Fogelstrand Linda, Wei Stella Y, Busayavalasa Kiran, Liu Kui, Liu Viktor M
Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden ; Laboratory of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden ; Section for Haematology and Coagulation, Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
Exp Hematol Oncol. 2016 Jun 30;5:17. doi: 10.1186/s40164-016-0047-0. eCollection 2015.
PTEN acts as a phosphatase for PIP3 and negatively regulates the PI3K/AKT pathway, and p27(KIP1) is a cyclin-dependent kinase inhibitor that regulates the G1 to S-phase transition by binding to and regulating the activity of cyclin-dependent kinases. Genetic alterations of PTEN or CDKN1B (p27(KIP1)) are common in hematological malignancies. To better understand how mutations in these two genes might cooperate in leukemogenesis, we inactivated both genes in the hematological compartment in mice. Here, we show that the combined inactivation of Pten and Cdkn1b results in a more severe myeloproliferative neoplasm phenotype associated with lower hemoglobin, enlarged spleen and liver, and shorter lifespan compared to inactivation of Pten alone. More severe anemia and increased myeloid infiltration and destruction of the spleen contributed to the earlier death of these mice, and elevated p-AKT, cyclin D1, and cyclin D3 might contribute to the development of this phenotype. In conclusion, PTEN and p27(KIP1) cooperate in tumor suppression in the hematological compartment.
PTEN作为PIP3的磷酸酶，对PI3K/AKT信号通路起负调控作用，而p27（KIP1）是一种细胞周期蛋白依赖性激酶抑制剂，通过与细胞周期蛋白依赖性激酶结合并调节其活性来调控G1期到S期的转换。PTEN或CDKN1B（p27（KIP1））的基因改变在血液系统恶性肿瘤中很常见。为了更好地理解这两个基因的突变如何在白血病发生过程中协同作用，我们在小鼠的血液系统中使这两个基因失活。在此，我们表明，与单独使Pten失活相比，Pten和Cdkn1b的联合失活导致更严重的骨髓增殖性肿瘤表型，表现为血红蛋白降低、脾脏和肝脏肿大以及寿命缩短。更严重的贫血、骨髓浸润增加以及脾脏破坏导致这些小鼠更早死亡，而p-AKT、细胞周期蛋白D1和细胞周期蛋白D3升高可能促成了这种表型的发展。总之，PTEN和p27（KIP1）在血液系统中协同发挥肿瘤抑制作用。
