Abstract
The non-genotoxic nature of proteasome inhibition makes it an attractive therapeutic option for the treatment of pediatric malignancies. We recently described the small molecule VLX1570 as an inhibitor of proteasome deubiquitinase (DUB) activity that induces proteotoxic stress and apoptosis in cancer cells. Here we show that acute lymphoblastic leukemia (ALL) cells are highly sensitive to treatment with VLX1570, resulting in the accumulation of polyubiquitinated proteasome substrates and loss of cell viability. VLX1570 treatment increased the levels of a number of proteins, including the chaperone HSP70B’, the oxidative stress marker heme oxygenase-1 (HO-1) and the cell cycle regulator p21Cip1. Unexpectedly, polyubiquitin accumulation was found to be uncoupled from ER stress in ALL cells. Thus, increased phosphorylation of eIF2α occurred only at supra-pharmacological VLX1570 concentrations and did not correlate with polyubiquitin accumulation. Total cellular protein synthesis was found to decrease in the absence of eIF2α phosphorylation. Furthermore, ISRIB (Integrated Stress Response inhibitor) did not overcome the inhibition of protein synthesis. We finally show that VLX1570 can be combined with L-asparaginase for additive or synergistic antiproliferative effects on ALL cells. We conclude that ALL cells are highly sensitive to the proteasome DUB inhibitor VLX1570 suggesting a novel therapeutic option for this disease.
Highlights
Introductionacute lymphoblastic leukemia (ALL), constitutes ~85 percent of all leukemias in children, with a peak incidence at 2–5 years of age [1, 2]
Acute lymphoblastic leukemia, acute lymphoblastic leukemia (ALL), constitutes ~85 percent of all leukemias in children, with a peak incidence at 2–5 years of age [1, 2]
We investigated the effect of the proteasome deubiquitinase (DUB) inhibitor VLX1570 on the viability of 9 different ALL cell lines over 72 hours using the MTT viability assay
Summary
ALL, constitutes ~85 percent of all leukemias in children, with a peak incidence at 2–5 years of age [1, 2]. B-cell lineage ALL is the most common form (80–85%) with the remaining 15–20% derived from a T cell lineage [1]. As ALL progresses, leukemic blasts crowd out normal cells in the bone marrow resulting in disruptions in normal blood cell homeostasis and anemia [3]. Dependent on the type (i.e. B-cell or T-cell lineage), ALL cells show chromosome translocations with disruption of the genes encoding the Ig or TCR receptor and the breakpoint region [4]. A number of different fusion genes have been described, resulting in the generation of novel fusion proteins, many of which are implicated in aberrant transcriptional activation, such as the TEL/AML1 fusion prevalent in pediatric ALL cases [5]. In addition to gross genetic changes, point mutations in NOTCH, FBXW7 and JAK1 are frequent in ALL [6, 7]
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