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<p>Metabolic reprogramming of amino acids represents a vulnerability in cancer cells, yet the mechanisms underlying serine metabolism in acute myeloid leukemia (AML) and leukemia stem/initiating cells (LSCs/LICs) remain unclear. Here, we identify RNA <i>N</i><sup>6</sup>-methyladenosine (m<sup>6</sup>A) modification as a key regulator of serine biosynthesis in AML. Using a CRISPR/Cas9 screen, we find that depletion of m<sup>6</sup>A regulators IGF2BP3 or METTL14 sensitizes AML cells to serine and glycine (SG) deprivation. IGF2BP3 recognizies m<sup>6</sup>A on mRNAs of key serine synthesis pathway (SSP) genes (e.g., <i>ATF4</i>, <i>PHGDH</i>, <i>PSAT1</i>), stabilizing these transcripts and sustaining serine production to meet the high metabolic demand of AML cells and LSCs/LICs. IGF2BP3 silencing combined with dietary SG restriction potently inhibits AML in vitro and in vivo, while its deletion spares normal hematopoiesis. Our findings reveal the critical role of m<sup>6</sup>A modification in the serine metabolic vulnerability of AML and highlight the IGF2BP3/m<sup>6</sup>A/SSP axis as a promising therapeutic target.</p>

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m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月6日

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  • Feng Huang,
  • Yushuai Wang,
  • Xiuxin Zhang,
  • Weiwei Gao,
  • Jingwen Li,
  • Ying Yang,
  • Hongjie Mo,
  • Emily Prince,
  • Yifei Long,
  • Jiacheng Hu,
  • Chuang Jiang,
  • Yalin Kang,
  • Zhenhua Chen,
  • Yueh-Chiang Hu,
  • Chengwu Zeng,
  • Lu Yang,
  • Chun-Wei Chen,
  • Jianjun Chen,
  • Huilin Huang,
  • Hengyou Weng

摘要

Metabolic reprogramming of amino acids represents a vulnerability in cancer cells, yet the mechanisms underlying serine metabolism in acute myeloid leukemia (AML) and leukemia stem/initiating cells (LSCs/LICs) remain unclear. Here, we identify RNA N6-methyladenosine (m6A) modification as a key regulator of serine biosynthesis in AML. Using a CRISPR/Cas9 screen, we find that depletion of m6A regulators IGF2BP3 or METTL14 sensitizes AML cells to serine and glycine (SG) deprivation. IGF2BP3 recognizies m6A on mRNAs of key serine synthesis pathway (SSP) genes (e.g., ATF4, PHGDH, PSAT1), stabilizing these transcripts and sustaining serine production to meet the high metabolic demand of AML cells and LSCs/LICs. IGF2BP3 silencing combined with dietary SG restriction potently inhibits AML in vitro and in vivo, while its deletion spares normal hematopoiesis. Our findings reveal the critical role of m6A modification in the serine metabolic vulnerability of AML and highlight the IGF2BP3/m6A/SSP axis as a promising therapeutic target.