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Nuclear factor I-C overexpression promotes monocytic development and cell survival in acute myeloid leukemia

Rastogi, Namrata, Gonzalez, Juan Bautista Menendez, Srivastava, Vikas, Alanazi, Bader, Alanazi, Rehab N., Hughes, Owen M., O'Neill, Niamh S., Gilkes, Amanda, Ashley, Neil, Deshpande, Sumukh, Andrews, Robert, Mead, Adam, Rodrigues, Neil ORCID:, Knapper, Steven ORCID:, Darley, Richard ORCID: and Tonks, Alex ORCID: 2023. Nuclear factor I-C overexpression promotes monocytic development and cell survival in acute myeloid leukemia. Leukemia 37 , pp. 276-287. 10.1038/s41375-022-01801-z

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Nuclear factor I-C (NFIC) belongs to a family of NFI transcription factors that binds to DNA through CAATT-boxes and are involved in cellular differentiation and stem cell maintenance. Here we show NFIC protein is significantly overexpressed in 69% of acute myeloid leukemia patients. Examination of the functional consequences of NFIC overexpression in HSPCs showed that this protein promoted monocytic differentiation. Single-cell RNA sequencing analysis further demonstrated that NFIC overexpressing monocytes had increased expression of growth and survival genes. In contrast, depletion of NFIC through shRNA decreased cell growth, increased cell cycle arrest and apoptosis in AML cell lines and AML patient blasts. Further, in AML cell lines (THP-1), bulk RNA sequencing of NFIC knockdown led to downregulation of genes involved in cell survival and oncogenic signaling pathways including mixed lineage leukemia-1 (MLL-1). Lastly, we show that NFIC knockdown in an ex vivo mouse MLL::AF9 pre-leukemic stem cell model, decreased their growth and colony formation and increased expression of myeloid differentiation markers Gr1 and Mac1. Collectively, our results suggest that NFIC is an important transcription factor in myeloid differentiation as well as AML cell survival and is a potential therapeutic target in AML.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Publisher: Nature Publishing Group
ISSN: 1476-5551
Date of First Compliant Deposit: 19 December 2022
Date of Acceptance: 15 December 2022
Last Modified: 07 Dec 2023 17:32

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