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.
Bibliographical noteFunding 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.).