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Review
. 2006 Oct 9;95(7):775-81.
doi: 10.1038/sj.bjc.6603317. Epub 2006 Sep 5.

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

D Perrotti  1 , P Neviani
Affiliations
Review

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

D Perrotti et al. Br J Cancer. .

Abstract

The deregulated kinase activity of p210-BCR/ABL oncoproteins, hallmark of chronic myelogenous leukaemia (CML), induces and sustains the leukaemic phenotype, and contributes to disease progression. Imatinib mesylate, a BCR/ABL kinase inhibitor, is effective in most of chronic phase CML patients. However, a significant percentage of CML patients develop resistance to imatinib and/or still progresses to blast crisis, a disease stage that is often refractory to imatinib therapy. Furthermore, there is compelling evidence indicating that the CML leukaemia stem cell is also resistant to imatinib. Thus, there is still a need for new drugs that, if combined with imatinib, will decrease the rate of relapse, fully overcome imatinib resistance and prevent blastic transformation of CML. We recently reported that the activity of the tumour suppressor protein phosphatase 2A (PP2A) is markedly inhibited in blast crisis CML patient cells and that molecular or pharmacologic re-activation of PP2A phosphatase led to growth suppression, enhanced apoptosis, impaired clonogenic potential and decreased in vivo leukaemogenesis of imatinib-sensitive and -resistant (T315I included) CML-BC patient cells and/or BCR/ABL+ myeloid progenitor cell lines. Thus, the combination of PP2A phosphatase-activating and BCR/ABL kinase-inhibiting drugs may represent a powerful therapeutic strategy for blast crisis CML patients.

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Figures

Figure 1
Figure 1
Molecular Effects of PP2A activation on BCR/ABL and its downstream effectors. (Left) BCR/ABL inhibits PP2A activity by (A) inducing hnRNP A1 that, in turn, enhances SET expression, and (B) inducing PP2Ac Y307 phosphorylation. In BCR/ABL+ myeloid progenitor cells, suppression of PP2A phosphatase activity is required for sustained activation of mitogenic and survival signals, in part, mediated by the indicated BCR/ABL downstream effectors. (Right) Restored PP2A activity, achieved by SET downregulation, PP2Ac overexpression or treatment with PP2A activators (e.g. forskolin or 1,9-dideoxy-forskolin), impairs in vitro and in vivo wild-type and T315I BCR/ABL leukaemogenesis by antagonising the effects of BCR/ABL on its downstream signal transducers and promoting BCR/ABL inactivation and proteasome-dependent degradation.
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