The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein

Abstract

The oncogenic BCR/ABL kinase activity induces and maintains chronic myelogenous leukemia (CML). We show here that, in BCR/ABL-transformed cells and CML blast crisis (CML-BC) progenitors, the phosphatase activity of the tumor suppressor PP2A is inhibited by the BCR/ABL-induced expression of the PP2A inhibitor SET. In imatinib-sensitive and -resistant (T315I included) BCR/ABL+ cell lines and CML-BC progenitors, molecular and/or pharmacological activation of PP2A promotes dephosphorylation of key regulators of cell proliferation and survival, suppresses BCR/ABL activity, and induces BCR/ABL degradation. Furthermore, PP2A activation results in growth suppression, enhanced apoptosis, restored differentiation, impaired clonogenic potential, and decreased in vivo leukemogenesis of imatinib-sensitive and -resistant BCR/ABL+ cells. Thus, functional inactivation of PP2A is essential for BCR/ABL leukemogenesis and, perhaps, required for blastic transformation.

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

“…The in vivo forskolin and 1,9-dideoxy forskolin antileukaemic activity and the low toxicity are consistent with the long elimination half-life assessed in healthy individuals and with the absence of toxicity in mice treated with these compounds (Kikura et al, 2004;Neviani et al, 2005). Furthermore, the safety and therapeutic effects of these diterpenes are also suggested by the prolonged survival of SCID mice transplanted with wild-type or T315I BCR/ABL cells (50% of mice were alive after 25 weeks of treatment while untreated leukaemic mice died within 5 weeks), and by the lack of signs of toxicity or leukaemia after administration of these compound for 18 and 25 (our unpublished data) weeks at 4 and 8 mg kg À1 week À1 .…”

“…phosphorylation) of signalling molecules, like those involved in the RAS/MAPK, PI3K/Akt and STATs pathways, which control cell growth, survival and differentiation of haematopoietic cells by modulating the expression and/or activity of downstream effectors (Melo and Deininger, 2004;Perrotti et al, 2005) (Figure 1). In blast crisis, increased expression of the BCR/ ABL oncoprotein accounts for the block of differentiation, inactivation of factors with tumour suppressor activity and decreased genomic stability of the Ph 1 blasts Skorski, 2002;Trotta et al, 2003;Calabretta and Perrotti, 2004;Neviani et al, 2005). Thus, dependence on BCR/ABL expression is not only a characteristic of CML-CP but also of CML-BC; however, BCR/ABL-independent mechanisms also seem to contribute to disease progression and imatinib resistance in some CML cases (Donato et al, 2003;Dai et al, 2004).…”

PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail)

“…Hence, PP2A deregulation can result in several pathological conditions such as cancer [3][4][5][6][7] and Alzheimer's disease (AD) [1,2]. Moreover, several viruses use PP2A to deregulate cellular pathways in the host [1][2][3]8], underscoring the general importance of PP2A in signal transduction.…”

“…In vivo Tyr307 phosphorylation has been observed in several conditions: in Box 3. Stoichiometric balance and PP2A-subunit composition in cancer PP2A has a central role in protecting cells against tumorigenic transformation, and both the a and b isoforms of human A subunits have been identified as tumor suppressors [1][2][3][4][5][6][7]. Although mutations in PPP2R1B, which encodes Ab, are more common, mutations in PPP2R1A, which encodes Aa, occur at low frequency in human tumors.…”

“…Cancer-associated mutations have also been identified in PPP2R5C, which encodes PR61/B 0 g. In melanoma, an N-terminally truncated form of PR61/B 0 g1 is associated with increased metastasis and genetic instability [3] owing to impaired phosphatase activity towards paxillin and Hdm2 (human homolog of double minute 2), two proteins involved in oncogenic signaling pathways [3,36]. 3 fibroblasts in response to EGF, serum, interleukin-1, tumor necrosis factor a or insulin [1], in fibroblasts overexpressing pp60 v-src [1], and in chronic myelogenous leukemia cells that overexpress the PP2A inhibitor called SET [7]. Threonine phosphorylation occurs via the activity of an 'autophosphorylation-activated protein kinase', the identity of which is currently unknown.…”