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.

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
  • 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
  • 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