Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia
Michele Milella, … , Elihu Estey, Michael Andreeff
Michele Milella, … , Elihu Estey, Michael Andreeff
Published September 15, 2001
Citation Information: J Clin Invest. 2001;108(6):851-859. https://doi.org/10.1172/JCI12807.
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Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia

Abstract

The mitogen-activated protein kinase (MAPK) pathway regulates growth and survival of many cell types, and its constitutive activation has been implicated in the pathogenesis of a variety of malignancies. In this study we demonstrate that small-molecule MEK inhibitors (PD98059 and PD184352) profoundly impair cell growth and survival of acute myeloid leukemia (AML) cell lines and primary samples with constitutive MAPK activation. These agents abrogate the clonogenicity of leukemic cells but have minimal effects on normal hematopoietic progenitors. MEK blockade also results in sensitization to spontaneous and drug-induced apoptosis. At a molecular level, these effects correlate with modulation of the expression of cyclin-dependent kinase inhibitors (p27Kip1 and p21Waf1/CIP1) and antiapoptotic proteins of the inhibitor of apoptosis proteins (IAP) and Bcl-2 families. Interruption of constitutive MEK/MAPK signaling therefore represents a promising therapeutic strategy in AML.

Authors

Michele Milella, Steven M. Kornblau, Zeev Estrov, Bing Z. Carter, Hélène Lapillonne, David Harris, Marina Konopleva, Shourong Zhao, Elihu Estey, Michael Andreeff

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MEK inhibition downregulates antiapoptotic proteins of the IAP and Bcl-2...
MEK inhibition downregulates antiapoptotic proteins of the IAP and Bcl-2 families. (a) OCI-AML3, HL-60, and U937 cells were cultured under standard conditions for 48 hours in the presence of DMSO or PD98059 (20 μM), and then subjected to Western blot analysis with Ab’s specific for the indicated antiapoptotic proteins of IAP (survivin, XIAP) and Bcl-2 (Mcl-1, Bcl-XL, Bcl-2) families. Results are representative of one of three independent experiments. (b) The MAPK phosphorylation status of AML cell lines was assessed by Western blot analysis. The ratio of phosphorylated to total p42MAPK (Phospho/total p42MAPK) was then plotted against the percent reduction in survivin expression observed in the corresponding cell lines after PD98059 treatment, and regression analysis was performed (R2 = 0.9104, P = 0.012). Results are representative of one of three independent experiments.