Loss of PTEN expression leading to high Akt activation in human multiple myelomas

Mouse plasma cell tumor (PCT) and human multiple myeloma (MM) are terminal B-cell malignancies sharing many similarities. Our recent work demonstrated that activation of the insulin-like growth factor receptor (IGF-(R)/insuli n receptor substrate (IRS)/phosphatidylinositol 3' kinase (PI 3'K) pathway was evident in the tumor lines derived from both species. Although PI 3'K a ctivity was higher in mouse tumor lines than that in human tumors, activati on of AM serine/threonine kinase was markedly lower in mouse lines. This di screpancy prompted us to test the status of PTEN tumor suppressor gene, as it has been shown to be a negative regulator of PI 3'K activity. Although a ll the mouse lines expressed intact PTEN, 2 of the 4 human lines (Delta 47 and OPM2) possessing the highest Akt activity lost PTEN expression. Sequenc ing analysis demonstrated that the PTEN gene contains a deletion spacing fr om exon 3 to exon 5 or 6 in the Delta 47 line and from exon 3 to 7 in the O PM2 line. Restoration of PTEN expression suppressed IGF-I-induced Akt activ ity, suggesting that loss of PTEN is responsible for uncontrolled AM activi ty in these 2 lines. Despite the expression of PTEN with the concomitant lo w Akt activity in all mouse PCT lines, their p70S6K activities were general ly higher than those in 3 human MM lines, arguing for specific negative reg ulation of Akt, but not p70S6K by PTEN. These results suggest that p70S6K a nd AM may be differentially used by the plasma cell tumors derived from mic e and humans, respectively. (C) 2000 by The American Society of Hematology.