M⁶A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability.

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 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 S

SUBMITTER: Huang F 

PROVIDER: S-EPMC12056023 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature