PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanisms in haematological malignancies

PTEN is a novel tumour suppressor gene that encodes a dual-specificity phos phatase with homology to adhesion molecules tensin and auxillin, It recentl y has been suggested that PTEN dephosphorylates phosphatidylinositol 3,4,5- trisphosphate [PtdIns(3,4,5)P-3], which mediates growth factor-induced acti vation of intracellular signalling, in particular through the serine-threon ine kinase Akt, a known cell survival-promoting factor, PTEN has been mappe d to 10q23.3, a region disrupted in several human tumours including haemato logical malignancies. We have analysed PTEN in a series of primary acute le ukaemias and non-Hodgkin's lymphomas (NHLs) as well as in cell lines. We ha ve also examined whether a correlation could be found between PTEN and Akt levels in these samples. We show here that the majority of cell lines studi ed carries PTEN abnormalities. At the structural level, we found mutations and hemizygous deletions in 40% of these cell lines, while a smaller number of primary haematological malignancies, in particular NHLs, carries PTEN m utations. Moreover, one-third of the cell lines had low PTEN transcript lev els, and 60% of these samples had low or absent PTEN protein, which could n ot be attributed to gene silencing by hypermethylation, In addition, we fou nd that PTEN and phosphorylated Akt levels are inversely correlated in the large majority of the examined samples. These findings suggest that PTEN pl ays a role in the pathogenesis of haematological malignancies and that it m ight be inactivated through a wider range of mechanisms than initially cons idered. The finding that PTEN levels inversely correlate with phosphorylate d Akt supports the hypothesis that PTEN regulates PtdIns(3,4,5)P-3 and sugg ests a role for PTEN in apoptosis.