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. 2023 Aug;202(3):550-565.
doi: 10.1111/bjh.18878. Epub 2023 May 24.

MYC-induced cytidine metabolism regulates survival and drug resistance via cGas-STING pathway in mantle cell lymphoma

Jin-Hua Liang  1   2   3 , Yi-Min Ren  1   2   3 , Kai-Xin Du  1   2   3 , Rui Gao  4   5 , Zi-Wen Duan  1   2   3 , Jing-Ran Guo  1   2   3 , Tong-Yao Xing  1   2   3 , Wei-Ting Wang  1   2   3 , Li Wang  1   2   3 , Yan Wang  1   2   3 , Rong Wang  1   2   3 , Jian-Yong Li  1   2   3 , Wei Xu  1   2   3
Affiliations

MYC-induced cytidine metabolism regulates survival and drug resistance via cGas-STING pathway in mantle cell lymphoma

Jin-Hua Liang et al. Br J Haematol. 2023 Aug.

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.

Keywords: TP53 aberrancy; cytidine metabolism; dsDNA-cGAS-STING pathway; ibrutinib resistance; mantle cell lymphoma; prognosis.

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References

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