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.
Subject(s)
Blast Crisis/metabolism , Chromosomal Proteins, Non-Histone/physiology , Fusion Proteins, bcr-abl/physiology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Phosphoprotein Phosphatases/metabolism , Phosphoprotein Phosphatases/physiology , Transcription Factors/physiology , Animals , Antineoplastic Agents/pharmacology , Benzamides , Cell Line, Transformed , Colforsin/pharmacology , DNA-Binding Proteins , Enzyme Inhibitors/metabolism , Histone Chaperones , Humans , Imatinib Mesylate , In Vitro Techniques , K562 Cells , Leukemia/prevention & control , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Mice , Mice, SCID , Neoplasm Transplantation , Phosphoprotein Phosphatases/antagonists & inhibitors , Piperazines/pharmacology , Protein Phosphatase 2 , Pyrimidines/pharmacology , Tumor Cells, Cultured , Tumor Suppressor Proteins/antagonists & inhibitors , Tumor Suppressor Proteins/physiologyABSTRACT
Developmental pattern formation allows cells within a tissue or organ to coordinate their development and establish cell types in relationship to one another. To better characterize the developmental patterning events within one organ, the C. elegans hindgut, we have analyzed the expression pattern of several genes using green fluorescent protein-based reporter transgenes. In wild-type animals, these genes are expressed in subsets of hindgut cells rather than in individual cell types. In mutant animals, we find that some, but not all, genes expressed in cells with altered development exhibit a corresponding alteration of gene expression. The results are consistent with a model where a combination of factors contribute to each cell's fate, and address how developmental information converges to specify cell types.
