Expression of PTEN in PTEN-deficient multiple myeloma cells abolishes tumor growth in vivo

• Published in: Oncogene Vol. 19; no. 36; pp. 4091 - 4095
• Main Authors: GE, N.-L, RUDIKOFF, S
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 24-08-2000; Nature Publishing Group
• Subjects: AKT protein; Amino acids; Animals; Apoptosis; Biological and medical sciences; Bone marrow; Caspase 3; Caspases - metabolism; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cloning; Ectopic expression; Fundamental and applied biological sciences. Psychology; Gene deletion; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Immunoglobulins; Insulin-Like Growth Factor I - pharmacology; Insulin-like growth factors; Latency; Mice; Mice, SCID; Molecular and cellular biology; Multiple myeloma; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Mutation; Neoplasm Transplantation; Phosphatase; Phosphates; Phosphatidylinositol; phosphatidylinositol phosphate; Phosphatidylinositol phosphates; Phosphatidylinositol Phosphates - genetics; Phosphatidylinositol Phosphates - metabolism; Phosphoric Monoester Hydrolases - deficiency; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; Phosphorylation; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; PTEN gene; PTEN Phosphohydrolase; PTEN protein; Reverse Transcriptase Polymerase Chain Reaction; Sequence Deletion; Transfection; Tumor Cells, Cultured; Tumor Suppressor Proteins; Tumors; Human; Immunopathology; Phosphorylation; Multiple; Enzyme; Transferases; Malignant hemopathy; Myeloma; Carcinogenesis; Regulation(control); Cell line; Immunoglobulinopathy; Protein kinase; Lymphoproliferative syndrome; C-Onc gene; Tumor progression; Mutation; Tumor cell; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1203801

Biochemical abnormalities associated with the development of multiple myeloma have been difficult to define especially in terms of demonstrating an in vivo effect of suspected lesions. Herein, we have identified such a defect associated with lack of expression of PTEN, a cellular phosphatase involved in the regulation of phosphatidylinositol phosphates (PIP's). In myeloma cells, PIP's are required for phosphorylation of Akt, a key event leading to inhibition of apoptosis. Loss of PTEN results in a failure to de-phosphorylate PIP's and a corresponding increase in Akt phosphorylation. OPM-2 cells lacking PTEN expression have the highest level of Akt phosphorylation of eight lines examined. Loss of PTEN was found to be associated with a 630 bp deletion corresponding to amino acids 56 - 267. Ectopic expression of wild type PTEN in OPM-2 cells inhibited Akt phosphorylation which was correlated with an increase in apoptosis. The in vivo relevance of loss of PTEN expression was demonstrated by injecting control and wild type PTEN transfected OPM-2 cells into SCID mice. Tumors arose at an incidence of 100% in controls, but only 50% (and of smaller size and longer latency) in low PTEN expressing clones. Importantly, clones expressing high levels of PTEN failed to produce tumors even at five times the latency period of controls. These results demonstrate that PTEN deletion/mutation is responsible for in vivo growth of this tumor and suggests that PTEN regulation may play an important role in tumor development in a subset of multiple myeloma patients. Oncogene (2000) 19, 4091 - 4095