The mek/erk kinase module: A potential new target for aml therapy

Michèle Milella

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The MEK/ERK kinase module is a key integration point along the signal transduction cascade that links diverse extracellular stimuli to a wide array of cellular responses, including proliferation, differention, and survival. We have recently observed the constitutive ERK2 activation in over 70% of primary AML samples (Kornblau SM et al., Blood 94 suppl. 1, 1999, 68a). We therefore investigated the functional consequences of MEK inhibition in AML cell lines and primary AML samples. MEK blockade by either PD98059 or PD184352 dose- and time-dependently inhibited cell growth in OCI-AML3, HL-60 and, to a lesser extent, NB4 cells, whereas U937 and KG1 were only marginally affected. In cell lines sensitive to MEK inhibition, PD184352 was approximately 100fold more potent than PD98059 (IC50 0.06 and 5.5 mM, respectively, in HL-60 cells). Sensitivity to MEK inhibition closely correlated with the levels of constitutive ERK1/2 phosphorylation and enzymatic activity. MEK inhibition resulted in dose- and timedependent Gl arrest in sensitive, but not in resistant, cell lines. This effect was accompanied by upregulation of p27kipl and downregulation of p21wafl/cipl. Moreover, treatment with PD98059 induced apoptosis in OCI-AML3 cells and potently sensitized OCI-AML3, HL-60 and NB4 cell lines to retinoic acid- and Ara-C-induced apoptosis. This effect was accompanied by downregulation of the anti-apoptotic proteins Mcl-1 and survivin. Growth inhibition and induction of apoptosis following PD98059 treatment was observed in 11/ 16 and 10/16 primary AML samples, respectively. More importantly, PD98059 profoundly inhibited the clonogenic growth of primary AML blasts in 4/4 samples studied so far. Conversely, CD34+ cells from healthy donors (n=3) did not show significant decrease in viability, induction of apoptosis or impairment in clonogenic growth upon PD98059 treatment. In summary, our data provide the rationale for developing therapeutic strategies targeting the MEK/ERK kinase module in AML.

Original languageEnglish
Issue number11 PART I
Publication statusPublished - 2000

ASJC Scopus subject areas

  • Hematology


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