ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia.
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.
Perrotti
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Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, and The Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. danilo.perrotti@osumc.edu
Neviani
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D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides; D001752:Blast Crisis / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D016313:Genes, abl / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D010749:Phosphoprotein Phosphatases / Q000008:administration & dosage* / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage*; D054648:Protein Phosphatase 2; D051562:Proto-Oncogene Proteins c-bcr / Q000187:drug effects; D011743:Pyrimidines / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2