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

The mitogen-activated protein kinase (MAPK) pathway regulates growth and su rvival of many cell types, and its constitutive activation has been implica ted in the pathogenesis of a variety of malignancies. In this study we demo nstrate that small-molecule MEK inhibitors (PD98059 and PD184352) profoundl y impair cell growth and survival of acute myeloid leukemia (AML) cell line s and primary samples with constitutive MAPK activation. These agents abrog ate the clonogenicity of leukemic cells but have minimal effects on normal hematopoietic progenitors. MEK blockade also results in sensitization to sp ontaneous and drug-induced apoptosis. At a molecular level, these effects c orrelate with modulation of the expression of cyclin-dependent kinase inhib itors (p27(Kip1) and p21(Waf1/CIP1)) and anti-apoptotic proteins of the inh ibitor of apoptosis proteins (IAP) and Bcl-2 families. Interruption of cons titutive MEK/MAPK signaling therefore represents a promising therapeutic st rategy in AML.