Regulation of the kinase RSK1 by arsenic trioxide and generation of antileukemic responses.

Arsenic Trioxide (As2O3) is one of the most effective agents in the treatment of acute promyelocytic leukemia (APL), but has no significant efficacy in other forms of AML. The mechanisms of relative resistance of non-APL cells are not well understood, but emerging evidence suggests that activation of negative feedback regulatory loops and pathways contributes to such resistance. We provide evidence that a signaling cascade involving the kinase RSK1 is engaged in a negative feedback manner during arsenic-treatment of cells and exhibits regulatory effects on growth and survival of AML cells in response to treatment with As2O3. Our data demonstrate that pharmacological inhibition or molecular disruption of expression of RSK1 enhances As2O3-dependent apoptosis and/or growth inhibition of AML cells. Importantly, combination of a pharmacological inhibitor of RSK and As2O3 results in enhanced suppression of primary AML leukemic progenitors. Altogether, our findings suggest an important regulatory role for RSK1 in the generation of the effects of As2O3 in AML cells. They also raise the potential of RSK1 targeting in combination with As2O3 as a novel approach to promote antileukemic responses.