A sumoylation program is essential for maintaining the mitotic fidelity in proliferating mantle cell lymphoma cells

Mantle cell lymphoma (MCL) is a rare and highly variable subtype of B-cell non-Hodgkin’s lymphoma. The sumoylation pathway, which plays a role in post-translational protein modification, is known to be elevated in several cancers, including those affecting lymphoid tissue. Despite this, its specific role in the development and progression of MCL remains poorly understood.

To investigate this, researchers measured the levels of sumoylation enzymes and sumoylated proteins in MCL cell lines and patient-derived samples using single-cell RNA sequencing and immunoblotting. The sumoylation enzyme SAE2 was inhibited both genetically using shRNA and pharmacologically with the compound TAK-981, also known as subasumstat. The impact of SAE2 suppression on MCL cell growth and cell cycle dynamics was assessed through confocal and live-cell microscopy, along with flow cytometry. Additionally, protein targets of sumoylation in MCL were identified using immunoprecipitation and mass spectrometry.

Findings revealed a marked increase in the expression of sumoylation enzymes SAE1 and SAE2 in MCL cells, which was associated with poor clinical outcomes and activation of genes linked to mitosis. Inhibiting SAE2 with TAK-981 caused substantial cell death in MCL models both in vitro and in vivo, with disrupted mitotic processes emerging as a key mechanism. A mitosis-related sumoylation program was identified in MCL cells and found to be sensitive to TAK-981. Furthermore, treatment with TAK-981 led to the loss of centromeric localization of topoisomerase 2A, a gene that is highly expressed in MCL cells with elevated SAE1 and SAE2, likely contributing to the observed mitotic defects.

These results establish SAE2 as a promising therapeutic target in MCL and provide a foundation for future studies aimed at optimizing the use of desumoylation strategies in the treatment of MCL and other related blood cancers.