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

T. Hyun, A. Yam, S. Pece, X. Xie, J. Zhang, T. Miki, J. S. Gutkind, W. Li

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Abstract

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-IR)/insulin receptor substrate (IRS)/phosphatidylinositol 3' kinase (PI 3'K) pathway was evident in the tumor lines derived from both species. Although PI 3'K activity was higher in mouse tumor lines than that in human tumors, activation of Akt serine/threonine kinase was markedly lower in mouse lines. This discrepancy 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 all the mouse lines expressed intact PTEN, 2 of the 4 human lines (Δ47 and OPM2) possessing tile highest ANt activity lost PTEN expression. Sequencing analysis demonstrated that the PTEN gene contains a deletion spacing from exon 3 to exon 5 or 6 in the Δ47 line and from exon 3 to 7 in the OPM2 line. Restoration of PTEN expression suppressed IGF-1-induced Akt activity, suggesting that loss of PTEN is responsible for uncontrolled Akt activity in these 2 lines. Despite the expression of PTEN with the concomitant low Akt activity in all mouse PCT lines, their p70S6K activities were generally higher than those in 3 human MM lines, arguing for specific negative regulation of Akt, but not p70S6K by PTEN. These results suggest that p70S6K and Akt may be differentially used by the plasma cell tumors derived from mice and humans, respectively. (C) 2000 by The American Society of Hematology.

Original languageEnglish
Pages (from-to)3560-3568
Number of pages9
JournalBlood
Volume96
Issue number10
Publication statusPublished - Nov 15 2000

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ASJC Scopus subject areas

  • Hematology

Cite this

Hyun, T., Yam, A., Pece, S., Xie, X., Zhang, J., Miki, T., Gutkind, J. S., & Li, W. (2000). Loss of PTEN expression leading to high Akt activation in human multiple myelomas. Blood, 96(10), 3560-3568.