The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein
The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein
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DOI：
10.1016/j.ccr.2005.10.015
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发表时间：
2005-11-01
期刊：
影响因子：
50.3
通讯作者：
Perrotti, D
中科院分区：
文献类型：
--
作者：
Neviani, P;Santhanam, R;Perrotti, D
致癌性BCR/ABL激酶活性诱导和维持慢性髓性白血病（CML）。在BCR/ABL转化的细胞和CIVIL blast crisis （CML-BC）祖细胞中，BCR/ABL诱导的PP2A抑制剂SET表达可抑制肿瘤抑制因子PP2A的磷酸化酶活性。在伊马替尼敏感和耐药（包括T3151） BCR/ABL（+）细胞系和CML-BC祖细胞中，PP2A的分子和/或药理学激活可促进细胞增殖和存活关键调控因子的去磷酸化，抑制BCR/ABL活性。诱导BCR/ABL降解。此外，PP2A激活导致伊马替尼敏感和耐药的BCR/ABL（+）细胞生长抑制、细胞凋亡增强、分化恢复、克隆生成潜能受损、体内白血病发生减少。因此，PP2A的功能性失活对于BCR/ABL白血病的发生是必不可少的，并且可能是母细胞转化所必需的。
The oncogenic BCR/ABL kinase activity induces and maintains chronic myelogenous leukemia (CML). We show here that, in BCR/ABL-transformed cells and CIVIL 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 (T3151 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.