BloodSep 24, 2025

Removing a fusion gene stops leukemia stem cell traits and triggers two-way cell development in acute myeloid leukemia

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 7, 2026

Abstract

Primary acute myeloid leukemia (AML) cells with the t(8;21) chromosomal translocation depend on the RUNX1::RUNX1T1 fusion gene for maintaining their leukemic properties.

Silencing RUNX1::RUNX1T1 using small interfering RNA (siRNA)-loaded lipid nanoparticles leads to significant changes in chromatin accessibility.
This change redirects the leukemia-associated transcriptional network toward a myeloid differentiation program.
Single-cell analyses show that transcriptional reprogramming is linked to the reduction of immature stem and progenitor-like cell populations.
An increase in granulocytic and eosinophilic/mast cell-like populations is observed, which have diminished self-renewal capacity.
These results indicate the critical role of RUNX1::RUNX1T1 in sustaining AML and suggest the potential for targeting fusion gene expression in treatment.

Simplified

Chromosomal rearrangements that generate novel fusion genes are a hallmark of acute myeloid leukemia (AML). Depletion experiments in cell line models have suggested that their continued expression is required for maintaining their leukemic phenotype and that fusion genes therefore represent ideal cancer-specific therapeutic targets. However, the extent to which this result holds true for the different stages of hematopoietic development in primary cells and whether therapeutic agents can be efficiently delivered to those cells is still unclear. In this study, we demonstrate that primary AML cells harboring the chromosomal translocation t(8;21) are critically dependent on the corresponding fusion gene, RUNX1::RUNX1T1, to suppress differentiation and maintain stemness. Silencing RUNX1::RUNX1T1 expression using small interfering RNA (siRNA)-loaded lipid nanoparticles induces substantial changes in chromatin accessibility, thereby redirecting the leukemia-associated transcriptional network toward a myeloid differentiation program. Single-cell analyses reveal that this transcriptional reprogramming is associated with the depletion of immature stem and progenitor-like cell populations, accompanied by an expansion of granulocytic and eosinophilic/mast cell-like populations with impaired self-renewal capacity. These findings underscore the essential role of RUNX1::RUNX1T1 in sustaining AML and highlight the therapeutic potential of targeting fusion gene expression in primary AML cells.

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Competing interests

Conflict-of-interest disclosure: The authors declare no competing financial interests.

PubMed

Removing a fusion gene stops leukemia stem cell traits and triggers two-way cell development in acute myeloid leukemia

Abstract

Full Text

Funding

Competing interests

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