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Acute Leukemias

PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect

Leukemia volume 25, pages 606–614 (2011)Cite this article

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Abstract

Protein phosphatase 2A (PP2A) is a human tumor suppressor that inhibits cellular transformation by regulating the activity of several signaling proteins critical for malignant cell behavior. PP2A has been described as a potential therapeutic target in chronic myeloid leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia and B-cell chronic lymphocytic leukemia. Here, we show that PP2A inactivation is a recurrent event in acute myeloid leukemia (AML), and that restoration of PP2A phosphatase activity by treatment with forskolin in AML cells blocks proliferation, induces caspase-dependent apoptosis and affects AKT and ERK1/2 activity. Moreover, treatment with forskolin had an additive effect with Idarubicin and Ara-c, drugs used in standard induction therapy in AML patients. Analysis at protein level of the PP2A activation status in a series of patients with AML at diagnosis showed PP2A hyperphosphorylation in 78% of cases (29/37). In addition, we found that either deregulated expression of the endogenous PP2A inhibitors SET or CIP2A, overexpression of SETBP1, or downregulation of some PP2A subunits, might be contributing to PP2A inhibition in AML. In conclusion, our results show that PP2A inhibition is a common event in AML cells and that PP2A activators, such as forskolin or FTY720, could represent potential novel therapeutic targets in AML.

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Acknowledgements

This work was supported by the Ministerio Educación y Ciencia (SAF2005/06425 and AP2006-03038), Ministerio Ciencia e Innovación (PI081687), Departamento Salud del Gobierno de Navarra (14/2008), ISCIII-RTICC (RD06/0020/0078) and Fundación para la Investigación Médica Aplicada y UTE (Spain). We thank Dr Anna Sablina for useful discussion, Elizabeth Guruceaga of the Unit of Proteomics, Genomics and Bioinformatics of CIMA for bioinformatics analysis, and Leyre Urquiza and Marisol Gonzalez-Huarriz for technical assistance.

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Authors and Affiliations

  1. Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain

    I Cristóbal, L Garcia-Orti, C Cirauqui, M M Alonso & M D Odero

  2. Department of Genetics, University of Navarra, Pamplona, Navarra, Spain

    I Cristóbal, M J Calasanz & M D Odero

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  1. I Cristóbal
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  2. L Garcia-Orti
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Correspondence to M D Odero.

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Cristóbal, I., Garcia-Orti, L., Cirauqui, C. et al. PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect. Leukemia 25, 606–614 (2011). https://doi.org/10.1038/leu.2010.294

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