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<p>t(8;21) acute myeloid leukemia (AML) is driven by AML1-ETO, which undergoes alternative splicing to generate AML1-ETO9a (AE9a), a truncated isoform with enhanced leukemogenic activity. Although t(8;21) AML is considered favorable-risk, clinical outcomes are heterogeneous, and AE9a expression varies markedly among patients. How cells restrain this oncogenic isoform remains unclear. Here, we identify nonsense-mediated mRNA decay (NMD) as an isoform-specific buffer of AE9a dosage. Inclusion of the ETO9a cassette exon introduces premature termination codons and generates an NMD-sensitive transcript. In primary t(8;21) AML CD34⁺ hematopoietic stem and progenitor cells, AE9a inclusion inversely correlated with NMD-factor expression, and high EIF4A3 expression was associated with improved overall survival specifically in t(8;21) AML, but not in other AML subtypes. Pharmacological inhibition of SMG1 or EIF4A3 and genetic depletion of NMD factors increased AE9a abundance in t(8;21) AML cell lines and primary patient cells, with cytoplasmic transcript accumulation and increased AE9a protein. Conversely, EIF4A3 overexpression reduced AE9a RNA and protein, restrained t(8;21) AML cell growth, spared healthy CD34⁺ progenitor expansion, and enhanced idarubicin sensitivity. These findings define EIF4A3-dependent NMD as a checkpoint linking RNA surveillance to oncogenic fusion-isoform dosage, leukemic fitness, and chemosensitivity in t(8;21) AML, providing a mechanistic explanation for clinical heterogeneity in t(8;21) AML.</p><p></p>

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EIF4A3-dependent nonsense-mediated decay buffers AML1-ETO9a dosage and modulates outcome in t(8;21) acute myeloid leukemia

  • 期刊论文

  • 发表日期：

    2026年7月14日

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  • Min Zhang,
  • Yisheng Li,
  • Bin Zhang,
  • Chen Cai,
  • Shuyi Li,
  • Zhijie He,
  • Xiangyu Meng,
  • Chengguang Wang,
  • Weichao Ding,
  • Xiaoqi Wang,
  • Xingli Dong,
  • Yonghui Li,
  • Li Yu

摘要

t(8;21) acute myeloid leukemia (AML) is driven by AML1-ETO, which undergoes alternative splicing to generate AML1-ETO9a (AE9a), a truncated isoform with enhanced leukemogenic activity. Although t(8;21) AML is considered favorable-risk, clinical outcomes are heterogeneous, and AE9a expression varies markedly among patients. How cells restrain this oncogenic isoform remains unclear. Here, we identify nonsense-mediated mRNA decay (NMD) as an isoform-specific buffer of AE9a dosage. Inclusion of the ETO9a cassette exon introduces premature termination codons and generates an NMD-sensitive transcript. In primary t(8;21) AML CD34⁺ hematopoietic stem and progenitor cells, AE9a inclusion inversely correlated with NMD-factor expression, and high EIF4A3 expression was associated with improved overall survival specifically in t(8;21) AML, but not in other AML subtypes. Pharmacological inhibition of SMG1 or EIF4A3 and genetic depletion of NMD factors increased AE9a abundance in t(8;21) AML cell lines and primary patient cells, with cytoplasmic transcript accumulation and increased AE9a protein. Conversely, EIF4A3 overexpression reduced AE9a RNA and protein, restrained t(8;21) AML cell growth, spared healthy CD34⁺ progenitor expansion, and enhanced idarubicin sensitivity. These findings define EIF4A3-dependent NMD as a checkpoint linking RNA surveillance to oncogenic fusion-isoform dosage, leukemic fitness, and chemosensitivity in t(8;21) AML, providing a mechanistic explanation for clinical heterogeneity in t(8;21) AML.