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. 2005 Nov;8(5):355-68.
doi: 10.1016/j.ccr.2005.10.015.

The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein

Paolo Neviani  1 , Ramasamy Santhanam, Rossana Trotta, Mario Notari, Bradley W Blaser, Shujun Liu, Hsiaoyin Mao, Ji Suk Chang, Annamaria Galietta, Ashwin Uttam, Denis C Roy, Mauro Valtieri, Rebecca Bruner-Klisovic, Michael A Caligiuri, Clara D Bloomfield, Guido Marcucci, Danilo Perrotti
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Free article

The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein

Paolo Neviani et al. Cancer Cell. 2005 Nov.
Free article

Abstract

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.

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