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Background <p>NOP2/Sun RNA methyltransferase family member 2 (NSUN2) catalyzes 5-methylcytosine (m<sup>5</sup>C) modifications in tRNA, rRNA, and mRNA, playing critical roles in various malignancies. However, its expression and functional relevance in B-acute lymphoblastic leukemia (B-ALL) remain largely undefined.</p> Methods <p>Lineage-negative progenitor cells from <i>Nsun2</i> knockout (Δ/Δ) and wild-type (fl/fl) mice were used to generate BCR-ABL (P190)-driven murine B-ALL model. Furthermore, RNA sequencing (RNA-seq) was performed to identify NSUN2 targets. Cell proliferation, apoptosis, and colony formation, and global protein synthesis were measured in B-ALL cells with <i>NSUN2</i> deficiency.</p> Results <p>Here, we found that NSUN2 expression was significantly higher in bone marrow (BM) cells from B-ALL patients than normal controls (NCs). Knockdown of <i>NSUN2</i> reduced m<sup>5</sup>C amounts and induced ferroptosis and apoptosis in B-ALL cells. Moreover, <i>Nsun2</i> knockout significantly suppressed the leukemic burden and extended the OS in the murine B-ALL model in vivo. RNA-seq and subsequent studies identified ferritin heavy chain 1 (FTH1) as a downstream target of NSUN2. NSUN2 depletion sensitized B-ALL cells to ferroptosis induction via inhibiting FTH1 expression. In addition, overexpression of FTH1 rescued the ferroptosis and apoptosis induced by <i>NSUN2</i> knockdown. Mechanistically, <i>NSUN2</i> knockdown reduced m<sup>5</sup>C modifications on 3'UTR of <i>FTH1</i> mRNA, impairing its stability and reducing <i>FTH1</i> expression. Overexpression of wild-type (WT) NSUN2, but not its mutants, blocked <i>NSUN2</i> knockdown-induced cytotoxic effects, indicating that NSUN2 enhances leukemogenesis in an m<sup>5</sup>C-dependent manner. In addition, NSUN2 deficiency inhibited global protein synthesis in both human and murine B-ALL cells. In contrast, <i>Nsun2</i> depletion had a minimal impact on ferroptosis and protein synthesis in murine pre-B (B220<sup>+</sup>) cells, suggesting selective leukemic dependency.</p> Conclusions <p>Our results demonstrate that NSUN2 facilitates leukemogenesis by increasing FTH1 expression and enhancing global protein synthesis in an m<sup>5</sup>C-dependent manner. Targeting NSUN2 might provide a promising therapeutic strategy for B-ALL.</p>

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NSUN2 promotes leukemogenesis by ferritin heavy chain 1-mediated anti-ferroptosis and enhancing global protein synthesis in an m5C-dependent manner in B-acute lymphoblastic leukemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月28日

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  • Yigang Yuan,
  • Min Li,
  • Xuanyu Yu,
  • Chen Meng,
  • Shirui Yu,
  • Xinyao Chen,
  • Shixin Zhang,
  • Liuzhi Shi,
  • Xiaoyi Qin,
  • Ziyang Huang,
  • Chongyun Xing,
  • Shanhu Qian,
  • Bin Zhou,
  • Shenmeng Gao

摘要

Background

NOP2/Sun RNA methyltransferase family member 2 (NSUN2) catalyzes 5-methylcytosine (m5C) modifications in tRNA, rRNA, and mRNA, playing critical roles in various malignancies. However, its expression and functional relevance in B-acute lymphoblastic leukemia (B-ALL) remain largely undefined.

Methods

Lineage-negative progenitor cells from Nsun2 knockout (Δ/Δ) and wild-type (fl/fl) mice were used to generate BCR-ABL (P190)-driven murine B-ALL model. Furthermore, RNA sequencing (RNA-seq) was performed to identify NSUN2 targets. Cell proliferation, apoptosis, and colony formation, and global protein synthesis were measured in B-ALL cells with NSUN2 deficiency.

Results

Here, we found that NSUN2 expression was significantly higher in bone marrow (BM) cells from B-ALL patients than normal controls (NCs). Knockdown of NSUN2 reduced m5C amounts and induced ferroptosis and apoptosis in B-ALL cells. Moreover, Nsun2 knockout significantly suppressed the leukemic burden and extended the OS in the murine B-ALL model in vivo. RNA-seq and subsequent studies identified ferritin heavy chain 1 (FTH1) as a downstream target of NSUN2. NSUN2 depletion sensitized B-ALL cells to ferroptosis induction via inhibiting FTH1 expression. In addition, overexpression of FTH1 rescued the ferroptosis and apoptosis induced by NSUN2 knockdown. Mechanistically, NSUN2 knockdown reduced m5C modifications on 3'UTR of FTH1 mRNA, impairing its stability and reducing FTH1 expression. Overexpression of wild-type (WT) NSUN2, but not its mutants, blocked NSUN2 knockdown-induced cytotoxic effects, indicating that NSUN2 enhances leukemogenesis in an m5C-dependent manner. In addition, NSUN2 deficiency inhibited global protein synthesis in both human and murine B-ALL cells. In contrast, Nsun2 depletion had a minimal impact on ferroptosis and protein synthesis in murine pre-B (B220+) cells, suggesting selective leukemic dependency.

Conclusions

Our results demonstrate that NSUN2 facilitates leukemogenesis by increasing FTH1 expression and enhancing global protein synthesis in an m5C-dependent manner. Targeting NSUN2 might provide a promising therapeutic strategy for B-ALL.