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

doi:10.1016/j.ccr.2005.10.015

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

Cancer Cell. 2005 Nov;8(5):355-68. doi: 10.1016/j.ccr.2005.10.015.

Authors

Paolo Neviani¹, 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

Affiliation

¹ Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA.

PMID: 16286244
DOI: 10.1016/j.ccr.2005.10.015

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Benzamides
Blast Crisis / metabolism*
Cell Line, Transformed
Chromosomal Proteins, Non-Histone / physiology*
Colforsin / pharmacology
DNA-Binding Proteins
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

Substances

Antineoplastic Agents
Benzamides
Chromosomal Proteins, Non-Histone
DNA-Binding Proteins
Enzyme Inhibitors
Histone Chaperones
PPP2R1B protein, human
Piperazines
Ppp2r1b protein, mouse
Pyrimidines
SET protein, human
Transcription Factors
Tumor Suppressor Proteins
Colforsin
Imatinib Mesylate
Fusion Proteins, bcr-abl
Phosphoprotein Phosphatases
Protein Phosphatase 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding