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

Cells

Herman S. Overkleeft¹  Elmer Maurits¹  Andrej Besse²  Marianne Kraus²  Lenka Besse²  Max Mendez-Lopez²  Christoph Driessen² 

[1] Gorlaeus Laboratories, Leiden Institute of Chemistry, 2333 CC Leiden, The Netherlands;Laboratory of Experimental Oncology, Department of Oncology and Hematology, Cantonal Hospital St. Gallen, 9000 St. Gallen, Switzerland;

关键词: immunoproteasome;    chronic lymphocytic leukemia;    acute myeloid leukemia;    multiple myeloma;    plasma cell leukemia;    proteasome inhibitors;   

DOI  :  10.3390/cells11050838

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown