The role of the proteasome in AML

Abstract

Acute myeloid leukemia (AML) is deadly hematologic malignancy. Despite a well-characterized genetic and molecular landscape, targeted therapies for AML have failed to significantly improve clinical outcomes. Over the past decade, proteasome inhibition has been demonstrated to be an effective therapeutic strategy in several hematologic malignancies. Proteasome inhibitors, such as bortezomib and carfilzomib, have become mainstays of treatment for multiple myeloma and mantle cell lymphoma. In light of this success, there has been a surge of literature exploring both the role of the proteasome and the effects of proteasome inhibition in AML. Pre-clinical studies have demonstrated that proteasome inhibition disrupts proliferative cell signaling pathways, exhibits cytotoxic synergism with other chemotherapeutics and induces autophagy of cancer-related proteins. Meanwhile, clinical trials incorporating bortezomib into combination chemotherapy regimens have reported a range of responses in AML patients, with complete remission rates >80% in some cases. Taken together, this preclinical and clinical evidence suggests that inhibition of the proteasome may be efficacious in this disease. In an effort to focus further investigation into this area, these recent studies and their findings are reviewed here.

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.

Figure 2

The i-prot has distinct features compared with the constitutional proteasome. The i-prot is formed when the β1c, β2c and β5c subunits of the c-prot are replaced by β1i and β5i, respectively. The expression of these subunits is promoted – at least in part – by IFNγ and TNFα signaling. Once expressed, β1i and β5i associate with the chaperone protein POMP, which facilitates their incorporation into the proteasome. In AML, however, it has been demonstrated that β1i and β5i are sequestered by PRAS40, a component of mTORC1. Once mTORC1 is activated by any of a number of methods (hyperactivation of mTORC1 is a feature of numerous malignancies), it phosphorylates PRAS40 and releases β1i and β5i, thus facilitating the assembly of the i-prot. The incorporation of these different subunits alters the proteolytic substrate selectivity of the i-prot, granting the i-prot distinct functions as compared with the c-prot.

Figure 3

Structures of key proteasome inhibitors. Chemical structures of select clinical and investigational proteasome inhibitors: the dipeptide boronic acid bortezomib, tetrapeptide epoxyketone carfilzomib and tripeptide epoxyketone PR-957.