The tumor suppressor protein phosphatase 2A offsets the BCR/ABL oncogenic kinase

November 14, 2005

Scientists have uncovered an unexpected functional link between a phosphatase known to act as a tumor suppressor and BCR/ABL, a kinase that is intimately linked with cancer development and progression in specific forms of leukemia. The study, published in the November issue of Cancer Cell, provides fresh insight into the molecular mechanisms that are involved in induction and progression of chronic myelogenous leukemia (CML), and suggests a new strategy that may be an effective therapy for both treatment-sensitive and treatment-resistant forms of CML.

Normal cell growth and survival is dependent on an intricate balance between kinase and phosphatase activities. In the case of CML, constitutive activity of the BCR/ABL oncoprotein contributes to disease progression, including the transition from the chronic phase to the highly aggressive "blast crisis" (CML-BC) phase. In this work supported by The National Cancer Institute, NIH (Bethesda, MA) and The Congressionally Directed Chronic Myelogenous Leukemia Research Program (US Department of Defense), Dr. Danilo Perrotti from the Human Cancer Genetics Program at The Ohio State University Comprehensive Cancer Center and colleagues identified SET as a novel target of BCR/ABL. SET is a potent inhibitor of protein phosphatase 2A (PP2A), a phosphatase that is a known tumor suppressor. SET expression is enhanced during CML disease progression, resulting in a loss of PP2A activity during the blast crisis but not chronic phase of CML.

Loss of PP2A function has previously been linked to induction of cancer. The researchers showed that PP2A activation resulted in modulation of expression of key molecules that regulate cell survival, and PP2A activity resulted in growth suppression, cell differentiation, and enhanced apoptosis in both treatment-sensitive and treatment-resistant BCR/ABL cell lines. Dr. Perrotti's group further demonstrated that BCR/ABL itself is a target of PP2A, and that PP2A activity serves to inactivate BCR/ABL in patient CML-BC cells and BCR/ABL+ hematopoietic cell lines. These results suggest that hyperactivation of BCR/ABL and the progression of CML may be stimulated, at least in part, by BCR/ABL-dependent SET-mediated inhibition of PP2A tumor suppressor activity. Importantly, restoration of PP2A activity in CML-BC patient cells and cell lines with activated wild type and various forms of mutated BCR/ABL counteracted the development of leukemia. "Because of the Yin-Yang role of BCR/ABL and PP2A, pharmacologic enhancement of PP2A tumor suppressor activity may represent a novel therapeutic strategy for blast crisis and imatinib-resistant CML," offers Dr. Perrotti.
The researchers included Paolo Neviani, Ramasamy Santhanam, Rossana Trotta, Mario Notari, Bradley W. Blaser, Shujun Liu, Hsiaoyin Mao, Ji Suk Chang, Annamaria Galietta, Ashwin Uttam, Rebecca Bruner-Klisovic, Michael A. Caligiuri, Clara D. Bloomfield, Guido Marcucci, and Danilo Perrotti of the Ohio State University in Columbus, OH; Denis C. Roy, Université de Montreal, Montreal, Quebec; Mauro Valtieri, Istituto Superiore di Sanitá in Rome, Italy. This work was supported by NIH grants NCI CA095512 (D.P.), CA102031 (G.M.), and CA16058 and GRT8230100 (OSUCCC); the US Army, CML Research Program, DAMD17-03-1-0184 (D.P.); the Elsa Pardee Foundation for Cancer Research (D.P.); the Lauri Strauss Leukemia Research Foundation (D.P.); the Leukemia Clinical Research Foundation (C.D.B.); and Fonds de la Recherche en Sante du Quebec (D.C.R.).

Neviani et al.: "The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein." Publishing in Cancer Cell Vol 8, November 2005, pages 355-368. DOI 10.1016/j.ccr.2005.10.015

Cell Press

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