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 1

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MEK blockade inhibits the growth of leukemic, but not normal, hematopoie...
MEK blockade inhibits the growth of leukemic, but not normal, hematopoietic cells. (a) AML cell lines were assessed for MAPK phosphorylation by Western blot. (b) OCI-AML3 cells were exposed to DMSO (C) or PD98059 at the indicated doses for 6 hours. MAPK phosphorylation was then assessed by Western blot. (c) OCI-AML3 cells were treated as in b. MAPK enzymatic activity was measured by the ability to phosphorylate the specific substrate Elk1 in an in vitro kinase assay. (d) Mononuclear cells from patients 5 (filled circles), 9 (open squares), 10 (filled triangles), and 11 (open circles) were grown in colony assays in the presence of DMSO or PD98059 at the indicated doses. Results show AML blast colonies in the PD98059-treated group, expressed as a percentage of the colonies in the DMSO-treated group, and represent the average of quadruplicate cultures (SEM was constantly less than 10%). (e) MACS-sorted CD34+ cells from healthy donors were cultured in the presence of DMSO or 20 μM PD98059. Viability was then assessed by trypan blue dye exclusion. Results show viable cells in the PD98059-treated group, expressed as a percentage of the viable cells in the DMSO-treated group (four bars at left; each bar represents a single donor). Bone marrow cells from healthy donors were grown in colony assays in the presence of DMSO or 50 μM PD98059. Results show CFU-GM and burst-forming units–erythroid (BRU-E) in the PD98059-treated group, expressed as a percentage of the colonies in the DMSO-treated group (four bars at right; two donors).