Activation of protein phosphatase 2A in FLT3+ acute myeloid leukemia cells enhances the cytotoxicity of FLT3 tyrosine kinase inhibitors

Smith, A. M. and Dun, M. D. and Lee, E. M. and Harrison, C. and Kahl, R. and Flanagan, H. and Panicker, N. and Mashkani, B. and Don, A. S. and Morris, J. and Toop, H. and Lock, R. B. and Powell, J. A. and Thomas, D. and Guthridge, M. A. and Moore, A. and Ashman, L. K. and Skelding, K. A. and Enjeti, A. and Verrills, N. M. (2016) Activation of protein phosphatase 2A in FLT3+ acute myeloid leukemia cells enhances the cytotoxicity of FLT3 tyrosine kinase inhibitors. Oncotarget, 7 (30). pp. 47465-47478.

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Abstract

Constitutive activation of the receptor tyrosine kinase Fms-like tyrosine kinase 3 (FLT3), via co-expression of its ligand or by genetic mutation, is common in acute myeloid leukemia (AML). In this study we show that FLT3 activation inhibits the activity of the tumor suppressor, protein phosphatase 2A (PP2A). Using BaF3 cells transduced with wildtype or mutant FLT3, we show that FLT3-induced PP2A inhibition sensitizes cells to the pharmacological PP2A activators, FTY720 and AAL(S). FTY720 and AAL(S) induced cell death and inhibited colony formation of FLT3 activated cells. Furthermore, PP2A activators reduced the phosphorylation of ERK and AKT, downstream targets shared by both FLT3 and PP2A, in FLT3/ITD+ BaF3 and MV4-11 cell lines. PP2A activity was lower in primary human bone marrow derived AML blasts compared to normal bone marrow, with blasts from FLT3-ITD patients displaying lower PP2A activity than WT-FLT3 blasts. Reduced PP2A activity was associated with hyperphosphorylation of the PP2A catalytic subunit, and reduced expression of PP2A structural and regulatory subunits. AML patient blasts were also sensitive to cell death induced by FTY720 and AAL(S), but these compounds had minimal effect on normal CD34+ bone marrow derived monocytes. Finally, PP2A activating compounds displayed synergistic effects when used in combination with tyrosine kinase inhibitors in FLT3-ITD+ cells. A combination of Sorafenib and FTY720 was also synergistic in the presence of a protective stromal microenvironment. Thus combining a PP2A activating compound and a FLT3 inhibitor may be a novel therapeutic approach for treating AML.

Item Type: Article
Additional Information: Cited By :23 Export Date: 16 February 2020 Correspondence Address: Verrills, N.M.; School of Biomedical Sciences and Pharmacy, University of NewcastleAustralia; email: nikki.verrills@newcastle.edu.au
Uncontrolled Keywords: AML FLT3 FTY720 PP2A Tyrosine kinase inhibitor CD123 antigen CD135 antigen CD38 antigen fingolimod lestaurtinib midostaurin mitogen activated protein kinase okadaic acid phosphoprotein phosphatase 2A protein kinase B protein tyrosine kinase inhibitor quizartinib sorafenib sphingosine kinase 2 STAT3 protein stem cell factor receptor sunitinib carbanilamide derivative FLT3 protein, human nicotinamide phosphoprotein phosphatase 2 protein kinase inhibitor acute lymphoblastic leukemia acute myeloblastic leukemia apoptosis Article bone marrow cell cancer inhibition cancer survival CD34 selection cell death cell viability coculture colony formation drug antagonism drug cytotoxicity drug potentiation drug sensitization enzyme activation enzyme activity enzyme phosphorylation enzyme specificity human leukemogenesis myeloid leukemia cell line overall survival protein expression protein targeting signal transduction tumor suppressor gene acute myeloid leukemia analogs and derivatives animal antagonists and inhibitors enzymology mouse physiology tumor cell line Animals Cell Line, Tumor Fingolimod Hydrochloride fms-Like Tyrosine Kinase 3 Humans Leukemia, Myeloid, Acute Mice Niacinamide Phenylurea Compounds Protein Kinase Inhibitors Protein Phosphatase 2
Subjects: WH Hemic and Lymphatic System
Divisions: Mashhad University of Medical Sciences
Depositing User: mr lib4 lib4
Date Deposited: 26 Feb 2020 05:15
Last Modified: 26 Feb 2020 05:15
URI: http://eprints.mums.ac.ir/id/eprint/13219

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