The ratio of RUNX1-ETO oncoprotein to normal RUNX1 expression determines the balance between endothelial reprogramming and hematopoietic cell growth

2025 · doi:10.64898/2025.12.19.695648
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RUNX1-ETO induction in human ESCs irreversibly reprograms myeloid progenitors towards endothelial cells in a concentration-dependent manner, with equal RUNX1-ETO/RUNX1 ratios allowing some progenitor proliferation.

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⚙ AI-generated deep summary by claude@2026-07, 2026-07-14 · read from full text ⓘ

The study investigates whether the RUNX1-ETO oncoprotein from t(8;21) acute myeloid leukemia directly triggers endothelial signaling and whether this depends on AML progression, using a human embryonic stem cell line with an inducible RUNX1-ETO transgene. Single-cell analyses and integrated data showed that RUNX1-ETO induction reprograms ESC-derived myeloid progenitors toward endothelial cells, with endothelial reprogramming being concentration-dependent and irreversible. When RUNX1-ETO and normal RUNX1 are expressed at equal levels, a blood progenitor subpopulation escapes reprogramming and continues proliferating even in endothelial co-culture. The paper’s main limitation is that its model of oncogenic transcriptional activity uses an inducible ESC system rather than studying patient-derived AML directly. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

In t(8;21) acute myeloid leukemia (AML) the RUNX1 DNA binding domain is fused to the RUNX1T1 protein producing the RUNX1-ETO onco-fusion protein. We previously showed that t(8;21) leukemic stem cells aberrantly activate endothelial signalling pathways to initiate blast cell proliferation. Here, we employed a human embryonic stem cell (ESC) line expressing an inducible RUNX1-ETO transgene to determine whether RUNX1-ETO directly induces endothelial signalling pathways or whether it is dependent on AML progression. Using single cell analyses we show that RUNX1-ETO induction reprograms ESC-derived myeloid progenitors towards endothelial cells. Integrated data analysis demonstrates (i) that endothelial reprogramming is RUNX1-ETO concentration-dependent and irreversible, (ii) that when RUNX1-ETO and RUNX1 expression levels are equal, a sub-population of blood progenitors escapes reprogramming and (iii) keeps proliferating when co-cultured with endothelial cells. Our experiments provide important insights into the earliest stages of epigenetic reprogramming by oncogenic transcription factors in AML.
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Abstract In t(8;21) acute myeloid leukemia (AML) the RUNX1 DNA binding domain is fused to the RUNX1T1 protein producing the RUNX1-ETO onco-fusion protein. We previously showed that t(8;21) leukemic stem cells aberrantly activate endothelial signalling pathways to initiate blast cell proliferation. Here, we employed a human embryonic stem cell (ESC) line expressing an inducible RUNX1-ETO transgene to determine whether RUNX1-ETO directly induces endothelial signalling pathways or whether it is dependent on AML progression. Using single cell analyses we show that RUNX1-ETO induction reprograms ESC-derived myeloid progenitors towards endothelial cells. Integrated data analysis demonstrates (i) that endothelial reprogramming is RUNX1-ETO concentration-dependent and irreversible, (ii) that when RUNX1-ETO and RUNX1 expression levels are equal, a sub-population of blood progenitors escapes reprogramming and (iii) keeps proliferating when co-cultured with endothelial cells. Our experiments provide important insights into the earliest stages of epigenetic reprogramming by oncogenic transcription factors in AML. Competing Interest Statement Andrew Elefanty, Elizabeth Ng and Edouard Stanley are consultants for Retro Biosciences Inc. The company had no involvement in this study.

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last seen: 2026-05-20T01:45:00.602351+00:00