Bortezomib sensitivity of acute myeloid leukemia CD34+ cells can be enhanced by targeting the persisting activity of NF-κB and the accumulation of MCL-1

Abstract

Sustained NF-κB activation is often observed in acute myeloid leukemia (AML); therefore, proteasome inhibition has been proposed to efficiently target AML cells. In this study, we questioned whether leukemic stem cell-enriched CD34(+) cells are sensitive to the proteasome inhibitor bortezomib. Surprisingly, we observed in short-term and long-term culture assays that CD34(-) AML cells were more sensitive to bortezomib treatment compared with the CD34(+) AML cells at a clinical relevant dosage. Cotreatment with the apoptosis-inducing cytokine TRAIL did not enhance cell death in CD34(+) AML cells, in contrast to the effects in AML cell lines. The better survival of CD34(+) AML cells upon bortezomib treatment was due to a persisting NF-κB activity that could be overcome by the IKK inhibitor BMS-345541. This difference in sensitivity might be related to differences in NF-κB activation in AML CD34(+) versus CD34(-) cells, as suggested by a gene expression profiling study. Besides NF-κB, MCL-1 strongly determines the effectiveness of bortezomib. MCL-1 accumulated in CD34(+) AML cells upon bortezomib treatment and inhibition of MCL-1 by shRNA, or Obatoclax, significantly improved the sensitivity of CD34(+) AML cells to bortezomib. These results demonstrate that combining bortezomib with specific NF-κB or MCL-1 inhibitors might potentially target the leukemic stem cells.