2. Academic Validation
  3. CTP synthase 2 predicts inferior survival and mediates DNA damage response via interacting with BRCA1 in chronic lymphocytic leukemia

CTP synthase 2 predicts inferior survival and mediates DNA damage response via interacting with BRCA1 in chronic lymphocytic leukemia

  • Exp Hematol Oncol. 2023 Jan 12;12(1):6. doi: 10.1186/s40164-022-00364-0.
Xinting Hu 1 2 3 4,  Yang Han 5 2 3 4,  Jiarui Liu 5 2 3 4,  Hua Wang 5 2 3 4,  Zheng Tian 1 2 3 4,  Xin Zhang 1 2 3 4,  Ya Zhang 6 7 8 9,  Xin Wang 10 11 12 13 14
Affiliations

Affiliations

  • 1 Department of Hematology, Shandong Provincial Hospital, Shandong University, No.324, Jingwu Road, Jinan, 250021, Shandong, China.
  • 2 Shandong Provincial Engineering Research Center of Lymphoma, Jinan, 250021, Shandong, China.
  • 3 Branch of National Clinical Research Center for Hematologic Diseases, Jinan, 250021, Shandong, China.
  • 4 National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, 251006, China.
  • 5 Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324, Jingwu Road, Jinan, 250021, Shandong, China.
  • 6 Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324, Jingwu Road, Jinan, 250021, Shandong, China. maryzhangya@gmail.com.
  • 7 Shandong Provincial Engineering Research Center of Lymphoma, Jinan, 250021, Shandong, China. maryzhangya@gmail.com.
  • 8 Branch of National Clinical Research Center for Hematologic Diseases, Jinan, 250021, Shandong, China. maryzhangya@gmail.com.
  • 9 National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, 251006, China. maryzhangya@gmail.com.
  • 10 Department of Hematology, Shandong Provincial Hospital, Shandong University, No.324, Jingwu Road, Jinan, 250021, Shandong, China. xinw007@126.com.
  • 11 Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324, Jingwu Road, Jinan, 250021, Shandong, China. xinw007@126.com.
  • 12 Shandong Provincial Engineering Research Center of Lymphoma, Jinan, 250021, Shandong, China. xinw007@126.com.
  • 13 Branch of National Clinical Research Center for Hematologic Diseases, Jinan, 250021, Shandong, China. xinw007@126.com.
  • 14 National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, 251006, China. xinw007@126.com.
PMID: 36635772 DOI: 10.1186/s40164-022-00364-0
Abstract

Background: Cytidine triphosphate synthase 2 (CTPS2) is an essential metabolic Enzyme that catalyzes the biosynthesis of CTP. CTP synthases contribute to lymphocytes proliferation and tumorigenesis, but the role of CTPS2 in chronic lymphocytic leukemia (CLL) remains undefined.

Methods: In silico analysis was performed to quantified the expression and clinical analysis of CTPS2 and BRCA1. The expression was then validated on the internal sets. Loss-and gain-of-function assays were conducted to investigate the physiological phenotypes in CLL. RNA-seq was employed to probe the molecular mechanism of CTPS2.

Results: Herein, significant elevated expression of CTPS2 was observed in CLL patients compared to normal CD19 + B cells, which was verified in three independent cohorts. Furthermore, overexpression of CTPS2 was closely associated with undesired prognostic Indicators, including unmutated IGHV status and chromosome 11q23 deletion. Additionally, elevated CTPS2 expression predicted adverse overall survival and treatment-free survival with independent prognostic significance. Downregulation of CTPS2 in CLL cells exhibited attenuated cell proliferation, arrested G2/M cell cycle and increased Apoptosis. The addition of CTP or glutamine could reverse the above effects. Since RNA-seq showed the enrichment in DNA damage and response signaling, we subsequently found that silence of CTPS2 remarkably elevated DNA damage and decreased DNA repair. It was demonstrated that CTPS2 mediated DNA damage response via interacting with Breast Cancer 1 (BRCA1) protein in CLL through CoIP assays and rescued experiments.

Conclusions: Collectively, our study generated the novel findings that CTPS2 promoted CLL progression via DNA damage response and repair pathway. Targeting nucleotide metabolism potentially became an attractive strategy for treatment against CLL.

Keywords

Breast cancer associated 1; CTP synthase 2; Chronic lymphocytic leukemia; DNA damage response; Survival.

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