(Immuno)proteasomes as therapeutic target in acute leukemia

Abstract

The clinical efficacy of proteasome inhibitors in the treatment of multiple myeloma has encouraged application of proteasome inhibitor containing therapeutic interventions in (pediatric) acute leukemia. Here, we summarize the positioning of bortezomib, as first-generation proteasome inhibitor, and second-generation proteasome inhibitors in leukemia treatment from a preclinical and clinical perspective. Potential markers for proteasome inhibitor sensitivity and/or resistance emerging from leukemia cell line models and clinical sample studies will be discussed focusing on the role of immunoproteasome and constitutive proteasome (subunit) expression, PSMB5 mutations, and alternative mechanisms of overcoming proteolytic stress.

Keywords: Constitutive proteasome; Drug resistance; Immunoproteasome; Leukemia; Proteasome inhibition.

Fig. 1

Overview of cytotoxicity mechanism of chemotherapy drugs commonly used in acute leukemia treatment

Fig. 2

Subunit composition and inhibitors targeting of constitutive and immunoproteasomes. a 20S core proteasome and b fully assembled immunoproteasome with various cap proteins. c Clinically active and experimental inhibitors of constitutive- and/or immunoproteasome. Adapted from Verbrugge et al. 2015 [15]

Fig. 3

Overview of known molecular mechanisms involved in BTZ resistance. a Proteasome related resistance: relative down regulation of immunoproteasome as compared to constitutive proteasome (1) together with absolute upregulation of the constitutive proteasome (2) and mutation in the β5 subunit of the proteasome (3). b Alternative stress handling: upregulation of heat shock proteins (4) or changes in redox metabolism (5) which can prevent oxidative stress. Alternative handling ubiquitinated protein: exocytosis of ubiquitinated proteins in MARCKS-associated vesicles (6), and protein degradation through autophagy (7). c Activation pro-survival signaling: intrinsic activation of pro-survival pathways, e.g., AKT, NFκB, or MET (8) or through stimulation by direct interaction with stromal cells (9) or indirectly through soluble growth factors or interleukins (10). d Decreased apoptosis: downregulation (11) or mutation (12) of pro-apoptotic proteins. Finally, e, extrusion of BTZ via multidrug resistance efflux pump MDR1/Pgp (minor effect, more pronounced in CFZ resistance) (13). CP, constitutive proteasome; IP, immunoproteasome; MDR1, multidrug resistance protein 1; HSP, heat shock proteins; IGF1, insulin-like growth factor 1; IL, interleukin

Fig. 4

Clustering of PSMB5 mutations in several BTZ-resistant in vitro model systems [–, –81]