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

• Published in: Cancer cell Vol. 8; no. 5; pp. 355 - 368
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2005
• Subjects: Animals; Antineoplastic Agents - pharmacology; Benzamides; Blast Crisis - metabolism; Cell Line, Transformed; Chromosomal Proteins, Non-Histone - physiology; Colforsin - pharmacology; Enzyme Inhibitors - metabolism; Fusion Proteins, bcr-abl - physiology; Histone Chaperones; Humans; Imatinib Mesylate; In Vitro Techniques; K562 Cells; Leukemia - prevention & control; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Mice; Mice, SCID; Neoplasm Transplantation; Phosphoprotein Phosphatases - antagonists & inhibitors; Phosphoprotein Phosphatases - metabolism; Phosphoprotein Phosphatases - physiology; Piperazines - pharmacology; Protein Phosphatase 2; Pyrimidines - pharmacology; Transcription Factors - physiology; Tumor Cells, Cultured; Tumor Suppressor Proteins - antagonists & inhibitors; Tumor Suppressor Proteins - physiology
• ISSN: 1535-6108; 1878-3686
• 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.