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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Article

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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Figure 3

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MEK inhibition sensitizes to spontaneous and drug-induced apoptosis. (a)...
MEK inhibition sensitizes to spontaneous and drug-induced apoptosis. (a) OCI-AML3 cells were cultured in the presence of DMSO or PD98059 (20 μM) and stained for annexin V binding at the indicated times. Matched DMSO control at 96 hours is shown (C). Results are representative of one of three independent experiments. (b) Primary AML blasts were cultured in the presence of DMSO or PD98059 at the indicated doses for 96 hours. Apoptosis was then measured as percentage of cells with hypodiploid DNA content. Results are expressed as the net apoptosis induction (percentage of apoptosis in treated cells minus percentage of apoptosis in DMSO-treated cells) and represent the mean ± SD of the results obtained in three different patient samples (patients 3, 14, and 16). (c) AML cell lines were cultured for 96 hours in the presence of DMSO (white bars), 20 μM PD98059 (hatched bars), 1 μM ATRA (gray bars), or a combination of PD98059 and ATRA (black bars), and stained for annexin V binding. Results are representative of one of three independent experiments. (d) HL-60 cells were exposed to 10 μM Ara-C, washed, and cultured in the presence of DMSO (gray bars) or 20 μM PD98059 (black bars). White bars and hatched bars represent DMSO- and PD98059-treated HL-60 cells, respectively, in the absence of prior exposure to Ara-C. At the indicated times, cells were stained for annexin V binding. *DMSO-treated cultures were discontinued after 144 hours due to overgrowth. Results are representative of one of three independent experiments.