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Pharmacologic targeting of SUMOylation drives mitochondrial dysfunction and metabolic alterations in B cell Malignancies

ABSTRACT: Sumoylation is a post-translational modification process that is deregulated in cancer. We foundthat sumoylation machinery was overexpressed in diffuse large B-cell lymphoma (DLBCL).Treatment with TAK-981, a SUMO-activating enzyme (SAE) inhibitor, induced desumoylationof cytoplasmic and mitochondrial proteins, restricting growth of DLBCL and mantle celllymphoma (MCL) cell lines and primary cells. DLBCL cells treated with TAK-981 exhibitedDNA damage, G2 arrest and downregulation of DNA repair, MYC and OxPhos pathways. SAEinhibition disrupted mitochondrial integrity and function, accompanied by mitophagy and rapidaccumulation of ROS. Metabolomic profiling revealed decreases in Krebs cycle substrates, andSeahorse respirometry confirmed dramatic reduction in OxPhos upon SAE inhibition. CRISPR-Cas9 loss-of-function library screens implicated NFκB, TP53, DNA damage andcentromere/telomere gene pathways in resistance to SAE inhibition; knockout of TP53 or BAXrescued DLBCL cells from TAK-981-induced apoptosis. Treatment with TAK-981 prolongedsurvival of mice xenografted with DLBCL and MCL PDX tumors. Thus, sumoylation is apromising target in lymphoid malignancies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254913 | GEO | 2024/02/02

REPOSITORIES: GEO

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Project description:Mantle cell lymphoma (MCL) is a rare, highly heterogeneous type of B-cell non-Hodgkin’s lymphoma (NHL) driven by multiple genetic mutations disrupting cell cycle regulation and DNA damage response. Despite advances in therapy, novel treatment approaches are needed especially for highly proliferative MCL which has a particularly progressive clinical course even in the era of Bruton’s tyrosine kinase therapy. The sumoylation pathway is known to be upregulated in many cancers including lymphoid malignancies. However, little is currently known about the role of the sumoylation pathway and its oncogenic potential in MCL. We found extensive upregulation of the sumoylation pathway in MCL, particularly at the level of the E1 enzymes SAE1 and SAE2, with elevated expression levels of sumoylation enzyme components showing a worse prognosis and a strong positive correlation with cell cycle associated genes. Targeting the sumoylation pathway with TAK-981, a first in class sumoylation inhibitor currently being investigated in a clinical study of B-cell NHL in combination with rituximab (NCT04074330), resulted in potent loss of sumoylation in MCL cells with significant activity in in-vitro and in vivo models of MCL, including ibrutinib resistance cases. We found mitotic dysregulation to be an important, although not all encompassing mechanism of cell death upon loss of sumoylation of TAK-981 in MCL cells. We uncovered a diverse sumoylation program upon mitosis entry that was significantly reduced with TAK-981. Centromeric localization of the well known sumoylation substrate topoisomeraseIIA (TopIIA) was significantly abrogated upon mitosis entry, likely contributing at least in part to the mitotic dysregulation seen in MCL cells. This mechanism is highly relevant as TopIIA is significantly upregulated in MCL with SAE1/2 overexpression. Our study, in addition to the recently described immunomodulatory activity of TAK-981, not only validates SAE1/2 as a therapeutic target in MCL but also opens the door to further mechanistic work to uncover how to best use desumoylation therapy to treat MCL and other lymphoid malignancies.

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Pharmacologic targeting of SUMOylation drives mitochondrial dysfunction and metabolic alterations in B cell Malignancies

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