MYC-induced cytidine metabolism regulates survival and drug resistance via cGas-STING pathway in mantle cell lymphoma.
Br J Haematol
; 202(3): 550-565, 2023 08.
Article
em En
| MEDLINE
| ID: mdl-37226519
ABSTRACT
Lymphocyte proliferation and tumourigenesis are dependent on nucleotide synthesis to support DNA, RNA and phospholipid synthesis. Here, we identified that reprogramming of nucleotide metabolism as an important factor divides mantle cell lymphoma (MCL) into two groups with different transcriptional signalling pathways and varying prognoses. We establish a nucleotide metabolism-related prognostic model that includes six genes with different regression coefficients, which significantly predicts prognosis for MCL patients (p < 0.0001). Of these six genes, de novo CTP synthesis pathway enzyme CTPS1 whose inhibitor (STP938) is already in clinical trials for relapsed/refractory lymphomas (NCT05463263) has the highest regression coefficient. An increase in CTPS1 expression predicts adverse overall survival and progression-free survival with independent prognostic significance in 105 primary MCL samples and GEO database (GSE93291). CRISPR CTPS1 knockout causes DNA damage and proliferation defects in MCL. Additionally, MYC positively regulates CTPS1 expression, and TP53-aberrant and ibrutinib-resistant MCL cells also rely on cytidine metabolism. Furthermore, besides the obvious decreased CTP pool caused by CTPS1 deficiency, CTPS1 inhibition may also induce immune-related responses via activating dsDNA-cGAS-STING pathway, which plays a crucial role in impeding tumour growth in MCL patients.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfoma de Célula do Manto
Tipo de estudo:
Prognostic_studies
Limite:
Adult
/
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article