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

• Published in: British journal of haematology Vol. 202; no. 3; pp. 550 - 565
• Main Authors: Liang, Jin‐Hua, Ren, Yi‐Min, Du, Kai‐Xin, Gao, Rui, Duan, Zi‐Wen, Guo, Jing‐Ran, Xing, Tong‐Yao, Wang, Wei‐Ting, Wang, Li, Wang, Yan, Wang, Rong, Li, Jian‐Yong, Xu, Wei
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.08.2023
• Subjects: Clinical trials; CRISPR; CTP; cytidine metabolism; Cytidine triphosphate; DNA biosynthesis; DNA damage; Drug metabolism; Drug resistance; dsDNA‐cGAS‐STING pathway; Hematology; ibrutinib resistance; Lymphocytes; Lymphoma; Mantle cell lymphoma; Medical prognosis; Metabolism; Myc protein; p53 Protein; Phospholipids; Prognosis; Signal transduction; TP53 aberrancy; Transcription; Tumorigenesis; ibrutinib resistance; TP53 aberrancy; mantle cell lymphoma; cytidine metabolism; prognosis; dsDNA-cGAS-STING pathway
• ISSN: 0007-1048; 1365-2141; 1365-2141
• DOI: 10.1111/bjh.18878

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. In clinical practice, mantle cell lymphoma (MCL) can be classified into two groups based on nucleotide metabolism expression: a group with abnormal expression and adverse prognosis, and the other with superior prognosis. Abnormal nucleotide metabolism is characterized by limited cytidine metabolism enzyme CTPS1, which can be regulated by MYC at the transcriptional level, and plays key roles in MCL cell survival, outgrowth and drug resistance. CTPS1 supports MCL survival through two mechanisms (including TP53‐aberrant and BTKi‐resistant MCL cells): (1) supplying CTP pools; (2) reducing DNA damage and thereby inhibiting cGas‐STING pathway.