Journal
CANCER CELL
Volume 8, Issue 5, Pages 355-368Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2005.10.015
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Funding
- NCI NIH HHS [CA102031, CA16058, CA095512, R01 CA095512] Funding Source: Medline
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The oncogenic BCR/ABL kinase activity induces and maintains chronic myelogenous leukemia (CML). We show here that, in BCR/ABL-transformed cells and CIVIL 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 (T3151 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.
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