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

Paolo Neviani, 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

Research output: Contribution to journalArticlepeer-review

373 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)355-368
Number of pages14
JournalCancer Cell
Volume8
Issue number5
DOIs
StatePublished - Nov 2005

Bibliographical note

Funding Information:
We thank B. Calabretta, A. de la Chapelle, D. Guttridge, and S. Whitman for critical reading of the manuscript; L. Rush for histopathologic analysis; P. Paschka, M. Klisovic, and M. Guimond for technical support; and A. Ruppert for statistical advice. This work was supported by NIH grants NCI CA095512 (D.P.), CA102031 (G.M.), and CA16058 and GRT8230100 (OSU-CCC); 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.).

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