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Increased expression of RUNX3 inhibits normal human myeloid development

Menezes, Ana Catarina, Jones, Rachel, Shrestha, Alina, Nicholson, Rachael, Leckenby, Adam, Azevedo, Aleksandra, Davies, Sara, Baker, Sarah ORCID:, Gilkes, Amanda, Darley, Richard ORCID: and Tonks, Alex ORCID: 2022. Increased expression of RUNX3 inhibits normal human myeloid development. Leukemia 36 , pp. 1769-1780. 10.1038/s41375-022-01577-2

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RUNX3 is a transcription factor dysregulated in acute myeloid leukemia (AML). However, its role in normal myeloid development and leukemia is poorly understood. Here we investigate RUNX3 expression in both settings and the impact of its dysregulation on myelopoiesis. We found that RUNX3 mRNA expression was stable during hematopoiesis but decreased with granulocytic differentiation. In AML, RUNX3 mRNA was overexpressed in many disease subtypes, but downregulated in AML with core binding factor abnormalities, such as RUNX1::ETO. Overexpression of RUNX3 in human hematopoietic stem and progenitor cells (HSPC) inhibited myeloid differentiation, particularly of the granulocytic lineage. Proliferation and myeloid colony formation were also inhibited. Conversely, RUNX3 knockdown did not impact the myeloid growth and development of human HSPC. Overexpression of RUNX3 in the context of RUNX1::ETO did not rescue the RUNX1::ETO-mediated block in differentiation. RNA-sequencing showed that RUNX3 overexpression downregulates key developmental genes, such as KIT and RUNX1, while upregulating lymphoid genes, such as KLRB1 and TBX21. Overall, these data show that increased RUNX3 expression observed in AML could contribute to the developmental arrest characteristic of this disease, possibly by driving a competing transcriptional program favoring a lymphoid fate.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher: Springer Nature
ISSN: 0887-6924
Date of First Compliant Deposit: 13 April 2022
Date of Acceptance: 12 April 2022
Last Modified: 29 Jan 2024 07:17

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