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Interplay between transcription regulators RUNX1 and FUBP1 activates an enhancer of the oncogene c-KIT and amplifies cell proliferation.

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Debaize, Lydie 
Jakobczyk, Hélène 
Avner, Stéphane 
Gaudichon, Jérémie 
Rio, Anne-Gaëlle 


Runt-related transcription factor 1 (RUNX1) is a well-known master regulator of hematopoietic lineages but its mechanisms of action are still not fully understood. Here, we found that RUNX1 localizes on active chromatin together with Far Upstream Binding Protein 1 (FUBP1) in human B-cell precursor lymphoblasts, and that both factors interact in the same transcriptional regulatory complex. RUNX1 and FUBP1 chromatin localization identified c-KIT as a common target gene. We characterized two regulatory regions, at +700 bp and +30 kb within the first intron of c-KIT, bound by both RUNX1 and FUBP1, and that present active histone marks. Based on these regions, we proposed a novel FUBP1 FUSE-like DNA-binding sequence on the +30 kb enhancer. We demonstrated that FUBP1 and RUNX1 cooperate for the regulation of the expression of the oncogene c-KIT. Notably, upregulation of c-KIT expression by FUBP1 and RUNX1 promotes cell proliferation and renders cells more resistant to the c-KIT inhibitor imatinib mesylate, a common therapeutic drug. These results reveal a new mechanism of action of RUNX1 that implicates FUBP1, as a facilitator, to trigger transcriptional regulation of c-KIT and to regulate cell proliferation. Deregulation of this regulatory mechanism may explain some oncogenic function of RUNX1 and FUBP1.



Animals, Antineoplastic Agents, Base Sequence, Binding Sites, Bone Marrow Cells, Cell Line, Tumor, Cell Proliferation, Chromatin, Core Binding Factor Alpha 2 Subunit, DNA-Binding Proteins, Enhancer Elements, Genetic, Gene Expression Regulation, Leukemic, HEK293 Cells, Humans, Imatinib Mesylate, Mice, Mice, Inbred NOD, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Precursor Cells, B-Lymphoid, Primary Cell Culture, Protein Binding, Proto-Oncogene Proteins c-kit, RNA-Binding Proteins, Signal Transduction, Transcription, Genetic, Xenograft Model Antitumor Assays

Journal Title

Nucleic Acids Research

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Oxford University Press
Cancer Research UK (C14303/A17197)