Abstract
Proteasome inhibitors (PIs) are approved backbone treatments in multiple myeloma. More recently, inhibition of proteasome activity with the PI bortezomib has been clinically evaluated as a novel treatment strategy in pediatric acute lymphoblastic leukemia (ALL). However, we lack a marker that could identify ALL patients responding to PI-based therapy. By using a set of activity-based proteasome probes in conjunction with cytotoxicity assays, we show that B-cell precursor ALL (BCP-ALL), in contrast to T-ALL, demonstrates an increased activity of immunoproteasome over constitutive proteasome, which correlates with high ex vivo sensitivity to the PIs bortezomib and ixazomib. The novel selective PI LU015i-targeting immunoproteasome β5i induces cytotoxicity in BCP-ALL containing high β5i activity, confirming immunoproteasome activity as a novel therapeutic target in BCP-ALL. At the same time, cotreatment with β2-selective proteasome inhibitors can sensitize T-ALL to currently available PIs, as well as to β5i selective PI. In addition, levels of total and spliced forms of XBP1 differ between BCP-ALL and T-ALL, and only in BCP-ALL does high-spliced XBP1 correlate with sensitivity to bortezomib. Thus, in BCP-ALL, high immunoproteasome activity may serve as a predictive marker for PI-based treatment options, potentially combined with XBP1 analyses.
Highlights
Proteasome inhibitors (PIs), such as boronate-based bortezomib and ixazomib and epoxyketone-based carfilzomib, are approved therapeutic backbones in multiple myeloma (MM), a malignancy of terminally differentiated B-cells called plasma cells [1]
We used activity-binding probes (ABPs) labeling in a larger set of 28 BCP-acute lymphoblastic leukemia (ALL) and 21 T-ALL samples to directly assess the activity of the individual proteolytic proteasome and immunoproteasome β subunits, Cells 2021, 10, x FOR PEER REVIEW
Our findings demonstrate a positive correlation between the high activity of immunoproteasome subunits and high sensitivity to bortezomib and ixazomib for B-cell precursor ALL (BCP-ALL), in contrast to T-ALL
Summary
Proteasome inhibitors (PIs), such as boronate-based bortezomib and ixazomib and epoxyketone-based carfilzomib, are approved therapeutic backbones in multiple myeloma (MM), a malignancy of terminally differentiated B-cells called plasma cells [1]. The immunoproteasome has higher β5i and β2i subunit activity but lower β1i activity than the constitutive proteasome, resulting in the alternative cleavage of proteins into peptides that are presented by major histocompatibility complex (MHC) class I molecules [15]. The importance of the immunoproteasome as a target for interference in pediatric acute lymphoblastic leukemia (ALL) has been suggested earlier, based on increased expression of immunoproteasome subunits, together with functional studies showing promising cytotoxic activity of PIs in this disease [16,17,18]. We lack data that relate the activity of individual proteolytic subunits of the immunoproteasome versus the constitutive proteasome to the cytotoxic activity of PIs in the two major subsets of pediatric ALL, B-cell precursor ALL (BCP-ALL) and T-lineage ALL
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