Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia

M. Milella, S. M. Kornblau, Z. Estrov, B. Z. Carter, H. Lapillonne, D. Harris, M. Konopleva, S. Zhao, E. Estey, M. Andreeff

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish
Pages (from-to)851-859
Number of pages9
JournalJournal of Clinical Investigation
Volume108
Issue number6
DOIs
Publication statusPublished - 2001

ASJC Scopus subject areas

  • Medicine(all)

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