Dysregulation of survival and apoptosis pathways in acute myeloid leukemia: Targeting of NF-κB in AML

Acute myeloid leukemia is a hematological malignancy characterized by an increased number of white blood cells in the bone marrow. A rapid accumulation of these blasts results in the suppression of normal hematopoiesis leading to thrombocytopenia, granulocytopenia and/or anemia. Leukemic stem cells originate from normal hematopoietic stem cells in a process called leukemic transformation, which has been proposed to be a multi-step process. During the transformation cells have often acquired resistance to apoptosis which might not only result in the survival of these cells during transformation but also in resistance to chemotherapy. Bosman investigated which changes take place on the level of gene expression of apoptosis-related genes. He observed that TAK1 is higher expressed in leukemic stem-cells. This is potentially interesting as TAK1 is involved in the stimulation of survival by the activation of NF-kB. Specific inhibition of the gene expression of TAK1 resulted in apoptosis of leukemic stem cells and increased the survival of mice in different models. These data suggest that these cells are more dependent on the TAK1-NF-kB pathway for their survival.
Moreover, he investigated the cytotoxic effect of the first and second generation proteasome inhibitors, which block NF-kB activity, on leukemic stem cells. The data suggest that the proteasome inhibitor carfilzomib significantly induces apoptosis in leukemic stem cells. Further research is required to fully determine the effectivity of proteasome inhibition.