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.
Highlights
Hematological malignancies comprise of many subgroups including chronic and acute leukemia, lymphoma, and multiple myeloma (MM)
Medical Center, Amsterdam, The Netherlands leukemia, which can be divided into two major subgroups: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML)
proteasome inhibitors (PIs), e.g., Salinosporamide A (Marizomib) and the immunoproteasome inhibitor PR924. Another alternative protein disposal that is often related to drug resistance is autophagy. This process has been linked to BTZ resistance in several tumor models [85,86,87,88,89,90,91], it was not indicated in MARCKs overexpressing PI-resistant leukemia cells [73]
Summary
Hematological malignancies comprise of many subgroups including chronic and acute leukemia, lymphoma, and multiple myeloma (MM). The main reasons for treatment failure in both children and adults are intrinsic or acquired drug resistance in a subset of leukemia cells that are responsible for refractory disease or the development of relapse, which have a dismal prognosis. Leukemia cells feature many chromosomal and molecular aberrations, including chromosomal translocations (e.g., t(8:21), Inv(16)), hypo- and hyperdiploidy, activating mutations (e.g., FLT3/ITD, cKIT), and splicing defects, the latter leading to many different protein isoforms [7, 8]. Together, this leads to an aberrant protein expression, which imposes an inherent heavy burden on the UPS. This review provides a comprehensive overview on the molecular mechanisms of action and resistance to PIs in leukemia as well as current applications of PIs in clinical trials in leukemia patients
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