RUNX1-ETO oncoprotein levels determine the balance between endothelial reprogramming and pre-leukemic growth in a human ES cell model of AML.

IF 7.7 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2026-10-19 DOI:10.1016/j.celrep.2026.118157

Katerina Terolli, Floyd Hassenrueck, Alexander Maytum, Peter Keane, Lea Flippe, Sophie G Kellaway, Merel van der Meulen, Olaf T Heidenreich, Edouard G Stanley, Elizabeth S Ng, Andrew G Elefanty, Constanze Bonifer

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引用次数: 0

Abstract

In t(8;21) acute myeloid leukemia (AML), the RUNX1 DNA binding domain is fused to RUNX1T1 (ETO) producing the RUNX1-ETO fusion protein. We previously showed that t(8;21) leukemic stem cells aberrantly activate endothelial signaling pathways to initiate blast cell proliferation. Here, we employed a human embryonic stem cell (ESC) line carrying an inducible RUNX1-ETO transgene to determine whether endothelial signaling pathway activation depends on disease progression or is directly induced by RUNX1-ETO. Single-cell analyses demonstrate that RUNX1-ETO reprograms ESC-derived myeloid progenitors towards endothelial cells. We show (1) that endothelial reprogramming is RUNX1-ETO concentration-dependent and irreversible, (2) at similar RUNX1-ETO and RUNX1 expression levels, a sub-population of blood progenitors can escape reprogramming, and (3) keeps proliferating when co-cultured with endothelial cells. Our experiments highlight the role of cellular interactions in the maintenance of pre-leukemic cells and provide important insights into the earliest stages of genomic reprogramming by oncogenic transcription factors.

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RUNX1-ETO癌蛋白水平决定了AML人ES细胞模型中内皮重编程和白血病前期生长之间的平衡。

在急性髓性白血病（AML）中，RUNX1 DNA结合域与RUNX1T1 （ETO）融合，产生RUNX1-ETO融合蛋白。我们之前发现t（8;21）白血病干细胞异常激活内皮信号通路以启动母细胞增殖。在这里，我们使用了携带可诱导的RUNX1-ETO转基因的人胚胎干细胞（ESC）系来确定内皮信号通路的激活是依赖于疾病进展还是由RUNX1-ETO直接诱导。单细胞分析表明，RUNX1-ETO将esc来源的髓系祖细胞重编程为内皮细胞。我们发现(1)内皮细胞重编程是RUNX1- eto浓度依赖性且不可逆的；(2)在相似的RUNX1- eto和RUNX1表达水平下，血液祖细胞亚群可以逃避重编程；(3)与内皮细胞共培养时保持增殖。我们的实验强调了细胞相互作用在白血病前期细胞维持中的作用，并为致癌转录因子基因组重编程的早期阶段提供了重要的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.