Author/Authors :
Neviani، نويسنده , , Paolo and Santhanam، نويسنده , , Ramasamy and Trotta، نويسنده , , Rossana and Notari، نويسنده , , Mario and Blaser، نويسنده , , Bradley W. and Liu، نويسنده , , Shujun and Mao، نويسنده , , Hsiaoyin and Chang، نويسنده , , Ji Suk and Galietta، نويسنده , , Annamaria and Uttam، نويسنده , , Ashwin and Roy، نويسنده , , Denis C. and Valtieri، نويسنده , , Mauro and Bruner-Klisovic، نويسنده , , Rebecca and Caligiuri، نويسنده , , Michael A. and Bloomfield، نويسنده , , Clara D. and Marcucci، نويسنده , , Guido and Perrotti، نويسنده , , Danilo، نويسنده ,
Abstract :
Summary
cogenic 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.
