Scholarlink

<p>The N6-methyladenosine (m6A) modification plays an important role in the pathogenesis of various myeloid malignancies. However, its specific role in RAS mutation-induced myeloid malignancy is incompletely understood. In this study, we found that m6A methyltransferase methyltransferase-like 14 (METTL14) was highly expressed and associated with a shorter survival in a RAS-mutation myeloid malignancy, juvenile myelomonocytic leukemia (JMML). The knockout of METTL14 was revealed to significantly promote hematopoietic stem/progenitor cells (HSPCs) expansion and suppresses disease progression in a <i>Kras</i><sup><i>G12D/+</i></sup> mutation-induced mouse model of JMML. Moreover, knockout of METTL14 reduces hyperproliferation of <i>Kras</i><sup><i>G12D/+</i></sup> HSPCs and suppresses oncogenic <i>Kras</i><sup><i>G12D/+</i></sup>-induced myeloid disease in a cell-autonomous manner. Mechanistically, we revealed that the knockout of METTL14 reduced the autophagy levels of HSPCs by suppressing the transcription and translation of autophagy-related genes, such as autophagy-related gene 5 (<i>Atg5</i>) and autophagy-related gene 9 (<i>Atg9a</i>), through m6A modification. Furthermore, we found that the autophagy inhibition through knockout of ATG5 in <i>Kras</i><sup><i>G12D/+</i></sup> mutant mice promoted the expansion of HSPCs and inhibited the progression of leukemia disease, consistent with the phenotypes of knockout of METTL14. Finally, we observed that combined treatment with a m6A inhibitor and a MEK inhibitor synergistically suppressed JMML growth. Collectively, these findings highlight the critical role of METTL14 in JMML tumorigenesis and suggest that m6A modification represents a promising therapeutic target for this disease.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

The m6A methyltransferase METTL14 promotes oncogenic Kras induced juvenile myelomonocytic leukemia through dysregulating autophagy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月16日

查看全文
  • Peihua Zhang,
  • Keping Feng,
  • Xiao Yu,
  • Yi Yang,
  • Siyu Luo,
  • Qiao Li,
  • Hailong Zhang,
  • Yachun Jia,
  • Qiaoman Fei,
  • Xiaomin Ren,
  • Hongwei Liu,
  • Lin Li,
  • Dan Yang,
  • Gustave Munyurangabo,
  • Jingze Yue,
  • Qian Li,
  • Pengyu Zhang,
  • Lingqin Song,
  • Aili He,
  • Zhanping Lu,
  • Linlin Zhang,
  • Guangyao Kong

摘要

The N6-methyladenosine (m6A) modification plays an important role in the pathogenesis of various myeloid malignancies. However, its specific role in RAS mutation-induced myeloid malignancy is incompletely understood. In this study, we found that m6A methyltransferase methyltransferase-like 14 (METTL14) was highly expressed and associated with a shorter survival in a RAS-mutation myeloid malignancy, juvenile myelomonocytic leukemia (JMML). The knockout of METTL14 was revealed to significantly promote hematopoietic stem/progenitor cells (HSPCs) expansion and suppresses disease progression in a KrasG12D/+ mutation-induced mouse model of JMML. Moreover, knockout of METTL14 reduces hyperproliferation of KrasG12D/+ HSPCs and suppresses oncogenic KrasG12D/+-induced myeloid disease in a cell-autonomous manner. Mechanistically, we revealed that the knockout of METTL14 reduced the autophagy levels of HSPCs by suppressing the transcription and translation of autophagy-related genes, such as autophagy-related gene 5 (Atg5) and autophagy-related gene 9 (Atg9a), through m6A modification. Furthermore, we found that the autophagy inhibition through knockout of ATG5 in KrasG12D/+ mutant mice promoted the expansion of HSPCs and inhibited the progression of leukemia disease, consistent with the phenotypes of knockout of METTL14. Finally, we observed that combined treatment with a m6A inhibitor and a MEK inhibitor synergistically suppressed JMML growth. Collectively, these findings highlight the critical role of METTL14 in JMML tumorigenesis and suggest that m6A modification represents a promising therapeutic target for this disease.