Immunoproteasome Activity in Chronic Lymphocytic Leukemia as a Target of the Immunoproteasome-Selective Inhibitors.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Antineoplastic Agents*/pharmacology ; Leukemia, Lymphocytic, Chronic, B-Cell*/drug therapy ; Multiple Myeloma*/drug therapy; Humans ; Proteasome Endopeptidase Complex ; Proteasome Inhibitors/pharmacology ; Proteasome Inhibitors/therapeutic use

Targeting proteasome with proteasome inhibitors (PIs) is an approved treatment strategy in multiple myeloma that has also been explored pre-clinically and clinically in other hematological malignancies. The approved PIs target both the constitutive and the immunoproteasome, the latter being present predominantly in cells of lymphoid origin. Therapeutic targeting of the immunoproteasome in cells with sole immunoproteasome activity may be selectively cytotoxic in malignant cells, while sparing the non-lymphoid tissues from the on-target PIs toxicity. Using activity-based probes to assess the proteasome activity profile and correlating it with the cytotoxicity assays, we identified B-cell chronic lymphocytic leukemia (B-CLL) to express predominantly immunoproteasome activity, which is associated with high sensitivity to approved proteasome inhibitors and, more importantly, to the immunoproteasome selective inhibitors LU005i and LU035i, targeting all immunoproteasome active subunits or only the immunoproteasome β5i, respectively. At the same time, LU102, a proteasome β2 inhibitor, sensitized B-CLL or immunoproteasome inhibitor-inherently resistant primary cells of acute myeloid leukemia, B-cell acute lymphoblastic leukemia, multiple myeloma and plasma cell leukemia to low doses of LU035i. The immunoproteasome thus represents a novel therapeutic target, which warrants further testing with clinical stage immunoproteasome inhibitors in monotherapy or in combinations.

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21/20 Cantonal Hospital St Gallen Research Committee

Keywords: LU005i; LU035i; activity-based probes; acute myeloid leukemia; chronic lymphocytic leukemia; immunoproteasome; multiple myeloma; plasma cell leukemia; proteasome activity; proteasome inhibitors

0 (Antineoplastic Agents)
0 (Proteasome Inhibitors)
EC 3.4.25.1 (Proteasome Endopeptidase Complex)

Date Created: 20220310 Date Completed: 20220411 Latest Revision: 20220411

20221213

PMC8909520

10.3390/cells11050838

35269460