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

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 þ 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.

PKR Regulates B56α-mediated BCL2 Phosphatase Activity in Acute Lymphoblastic Leukemia-derived REH Cells

“…Activation of PP2A by a novel drug (i.e. FTY720) is currently being investigated in BCR-ABLE-positive ALL and chronic myeloid leukemia (42,43). It will be interesting to determine whether FTY720 activation of PP2A involves PKR.…”

“…Recently Neviani et al (41) demonstrated that PP2A is suppressed in the blast crisis phase of chronic myeloid leukemia but not during the chronic phase of the disease. BCR/ABL was shown to inactivate PP2A by enhancing expression of the potent PP2A inhibitor protein SET (41,42). Activation of PP2A by a novel drug (i.e.…”

Chronic myeloid leukemia – some topical issues

“…Altogether, these findings not only reinforce the importance of the PP2A tumor suppressor in the biology of Ph-positive leukemias 18 but, because FTY720 has been shown to be safe in Phase I-III clinical trials for multiple sclerosis and solid organ transplant patients, they strongly support the use of this PP2A activator as a novel therapeutic approach for CML-BC and Ph þ 1 ALL and, perhaps, for other cancers characterized by functional loss of PP2A activity.…”

“…Moreover, FTY720 treatment does not alter viability of non-transformed hematopoietic primary cell and cell lines but markedly impairs that of BCR-ABL-transformed cells (Santhanam et al, Blood 2006; 108; 89a, abstract). In fact, FTY720 induces caspasedependent apoptosis and markedly impairs the clonogenic potential of IM/dasatinib-sensitive and -resistant (T315I) p210 and p190 Bcr-Abl-expressing myeloid and lymphoid progenitor cell lines and of primary bone marrow CML- 18 Interestingly, the cytokine (IL-3 or IL-7)-dependent growth and differentiation of normal CD34 þ myeloid and CD34 þ /CD19 þ lymphoid progenitors are not affected by FTY720 treatment (Santhanam et al, Blood 2006; 108: 89a, abstract).…”

Dissecting Molecular Events in Thyroid Neoplasia Provides Evidence for Distinct Evolution of Follicular Thyroid Adenoma and Carcinoma

“…SET is an inhibitor of PP2A, 33 a tumor suppressor with functions in cell proliferation, survival, and differentiation. 34 The loss of PP2A has been associated with cell transformation. 35 Recently, PP2A was identified as a AKT phosphatase, which binds and dephosphorylates AKT in an agonist-dependent manner.…”