m<sup>6</sup>A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability.
basic_science · Level V
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- Record sourced from PubMed, PMID 40328743.
- Also identified by DOI 10.1038/s41467-025-58966-1 and PMC identifier 12056023.
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Abstract
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 N<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., 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 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.
Medical subject headings
- Leukemia, Myeloid, Acute
- Serine
- RNA-Binding Proteins
- Neoplastic Stem Cells
- Adenosine