Neviani Paolo, Santhanam Ramasamy, Trotta Rossana, Notari Mario, Blaser Bradley W, Liu Shujun, Mao Hsiaoyin, Chang Ji Suk, Galietta Annamaria, Uttam Ashwin, Roy Denis C, Valtieri Mauro, Bruner-Klisovic Rebecca, Caligiuri Michael A, Bloomfield Clara D, Marcucci Guido, Perrotti Danilo
Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA.
Cancer Cell. 2005 Nov;8(5):355-68. doi: 10.1016/j.ccr.2005.10.015.
The oncogenic BCR/ABL kinase activity induces and maintains chronic myelogenous leukemia (CML). We show here that, in BCR/ABL-transformed cells and CML blast crisis (CML-BC) progenitors, the phosphatase activity of the tumor suppressor PP2A is inhibited by the BCR/ABL-induced expression of the PP2A inhibitor SET. In imatinib-sensitive and -resistant (T315I included) BCR/ABL+ cell lines and CML-BC progenitors, molecular and/or pharmacological activation of PP2A promotes dephosphorylation of key regulators of cell proliferation and survival, suppresses BCR/ABL activity, and induces BCR/ABL degradation. Furthermore, PP2A activation results in growth suppression, enhanced apoptosis, restored differentiation, impaired clonogenic potential, and decreased in vivo leukemogenesis of imatinib-sensitive and -resistant BCR/ABL+ cells. Thus, functional inactivation of PP2A is essential for BCR/ABL leukemogenesis and, perhaps, required for blastic transformation.
致癌性BCR/ABL激酶活性诱导并维持慢性粒细胞白血病（CML）。我们在此表明，在BCR/ABL转化的细胞和CML急变期（CML-BC）祖细胞中，肿瘤抑制因子PP2A的磷酸酶活性受到BCR/ABL诱导的PP2A抑制剂SET表达的抑制。在对伊马替尼敏感和耐药（包括T315I）的BCR/ABL+细胞系和CML-BC祖细胞中，PP2A的分子和/或药理学激活促进细胞增殖和存活关键调节因子的去磷酸化，抑制BCR/ABL活性，并诱导BCR/ABL降解。此外，PP2A激活导致对伊马替尼敏感和耐药的BCR/ABL+细胞生长受抑、凋亡增强、分化恢复、克隆形成潜力受损以及体内白血病生成减少。因此，PP2A的功能失活对于BCR/ABL白血病发生至关重要，或许对于急变转化也是必需的。
