The TAK1-NF-κB axis as therapeutic target for AML

Development and maintenance of leukemia can partially be attributed to alterations in (anti) apoptotic gene expression. Genome-wide transcriptome analyses revealed that 89 apoptosis-associated genes were differentially expressed between patient acute myeloid leukemia (AML) CD34(+) cells and normal bone marrow (NBM) CD34(+) cells. Amongst these, TGF-β activated kinase 1 (TAK1) was strongly upregulated in AML CD34(+) cells. Genetic downmodulation or pharmacological inhibition of TAK1 activity strongly impaired primary AML cell survival and cobblestone formation in stromal co-cultures. TAK1 inhibition was mainly due to blockade of the NF-κB pathway, as TAK1 inhibition resulted in reduced levels of p-IκBα and p65 activity. Overexpression of a constitutive active variant of NF-κB partially rescued TAK1-depleted cells from apoptosis. Importantly, NBM CD34(+) cells were less sensitive to TAK1 inhibition compared to AML CD34(+) cells. Knockdown of TAK1 also severely impaired leukemia development in vivo and prolonged overall survival in a humanized xenograft mouse model. In conclusion, our results indicate that TAK1 is frequently overexpressed in AML CD34(+) cells, and that TAK1 inhibition efficiently target leukemic stem/progenitor cells in a NF-κB-dependent manner.