Figure 1.

The proteasome has several roles in AML. The primary function of the proteasome is the proteolytic degradation of ubiquitinated proteins. In AML, phosphorylation of IκBα targets this regulatory protein for ubiquitination and proteasomal degradation. Degradation of IκBα liberates NF-κB, allowing this transcription factor to translocate to the nucleus and promote the expression of pro-survival and proliferative gene products, including TNFα. Among other actions, TNFα binds to the tumor necrosis factor receptor and drives an autocrine signaling pathway, promoting further IκBα phosphorylation and creating a positive-feedback loop that reinforces NF-κB activity. Inhibition of proteasome activity by agents such as bortezomib or carfilzomib both disrupt this cycle, leading to cell death, and also induce other cellular mechanisms of protein degradation, such as autophagy. AML cells treated with bortezomib can sequester cytosolic proteins within membrane-bound vesicles called autophagosomes. These proteins, including the cancer-related proteins FLT3 and TRAF6, are then delivered to the lysosome for oxidative degradation.