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

Biochemical abnormalities associated with the development of multiple myelo ma hale been difficult to define especially in terms of demonstrating an ir t vivo effect of suspected lesions. Herein, we have identified such a defec t associated with lack of expression of PTEN, a cellular phosphatase involv ed 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-phospho rylate PIP's and a corresponding increase in Akt phosphorylation. OPM-2 cel ls 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 b p 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 expre ssion was demonstrated by injecting control and wild type PTEN transfected OPM-2 cells into SCID mice. Tumors arose at an incidence of 100% in control s, but only 50% (and of smaller size and longer latency) in lon PTEN expres sing clones. Importantly, clones expressing high le,els of PTEN failed to p roduce tumors even at five times the latency period of controls. These resu lts demonstrate that PTEN deletion/mutation is responsible for in vivo grow th of this tumor and suggests that PTEN regulation may play an important ro le in turner development in a subset of multiple myeloma patients.