Small-molecule SUMO inhibition for biomarker-informed B-cell lymphoma therapy.
Journal
Haematologica
ISSN: 1592-8721
Titre abrégé: Haematologica
Pays: Italy
ID NLM: 0417435
Informations de publication
Date de publication:
01 02 2023
01 02 2023
Historique:
received:
07
03
2022
pubmed:
23
9
2022
medline:
3
2
2023
entrez:
22
9
2022
Statut:
epublish
Résumé
Aberrant activity of the SUMOylation pathway has been associated with MYC overexpression and poor prognosis in aggressive B-cell lymphoma (BCL) and other malignancies. Recently developed small-molecule inhibitors of SUMOylation (SUMOi) target the heterodimeric E1 SUMO activation complex (SAE1/UBA2). Here, we report that activated MYC signaling is an actionable molecular vulnerability in vitro and in a preclinical murine in vivo model of MYC-driven BCL. While SUMOi conferred direct effects on MYC-driven lymphoma cells, SUMO inhibition also resulted in substantial remodeling of various subsets of the innate and specific immunity in vivo. Specifically, SUMOi increased the number of memory B cells as well as cytotoxic and memory T cells, subsets that are attributed a key role within a coordinated anti-tumor immune response. In summary, our data constitute pharmacologic SUMOi as a powerful therapy in a subset of BCL causing massive remodeling of the normal B-cell and T-cell compartment.
Identifiants
pubmed: 36134453
doi: 10.3324/haematol.2022.280995
pmc: PMC9890013
doi:
Substances chimiques
Proto-Oncogene Proteins c-myc
0
Biomarkers
0
UBA2 protein, human
0
Ubiquitin-Activating Enzymes
EC 6.2.1.45
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
555-567Références
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