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m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability
Feng Huang1,2,3, Yushuai Wang2, Xiuxin Zhang3,4
1The First Affiliated Hospital, The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, China.
Nature Communications
|May 6, 2025
Summary
RNA N6-methyladenosine (m6A) modification regulates serine synthesis in acute myeloid leukemia (AML). Depleting IGF2BP3, an m6A regulator, sensitizes AML cells to serine and glycine deprivation, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Pathways
Background:
- Amino acid metabolism reprogramming is a cancer vulnerability.
- Serine metabolism mechanisms in acute myeloid leukemia (AML) and leukemia stem/initiating cells (LSCs/LICs) are not fully understood.
Purpose of the Study:
- To investigate the role of RNA N6-methyladenosine (m6A) modification in regulating serine biosynthesis in AML.
- To identify key regulators and pathways involved in AML serine metabolism.
Main Methods:
- CRISPR/Cas9 screening to identify m6A regulators affecting AML cell survival.
- Analysis of IGF2BP3 binding to m6A-modified mRNAs of serine synthesis pathway (SSP) genes.
- Assessment of AML inhibition in vitro and in vivo using IGF2BP3 silencing and serine/glycine restriction.
Main Results:
- Depletion of m6A regulators IGF2BP3 or METTL14 sensitizes AML cells to serine and glycine (SG) deprivation.
- IGF2BP3 binds to m6A-modified mRNAs of SSP genes (e.g., ATF4, PHGDH, PSAT1), stabilizing them and sustaining serine production.
- IGF2BP3 silencing combined with dietary SG restriction potently inhibits AML in vitro and in vivo, sparing normal hematopoiesis.
Conclusions:
- RNA m6A modification is a critical regulator of the serine metabolic vulnerability in AML.
- The IGF2BP3/m6A/SSP axis represents a promising therapeutic target for AML treatment.
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