Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Base Sequence
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Binding Sites
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / metabolism
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Bone Marrow Cells / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chromatin / chemistry
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Chromatin / metabolism
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Core Binding Factor Alpha 2 Subunit / genetics*
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Core Binding Factor Alpha 2 Subunit / metabolism
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Enhancer Elements, Genetic*
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Gene Expression Regulation, Leukemic*
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HEK293 Cells
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Humans
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Imatinib Mesylate / pharmacology
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Mice
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Mice, Inbred NOD
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Precursor Cells, B-Lymphoid / drug effects
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Precursor Cells, B-Lymphoid / metabolism
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Precursor Cells, B-Lymphoid / pathology
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Primary Cell Culture
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Protein Binding
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Proto-Oncogene Proteins c-kit / genetics*
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Proto-Oncogene Proteins c-kit / metabolism
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RNA-Binding Proteins / genetics*
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RNA-Binding Proteins / metabolism
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Signal Transduction
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Transcription, Genetic
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Chromatin
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Core Binding Factor Alpha 2 Subunit
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DNA-Binding Proteins
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FUBP1 protein, human
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RNA-Binding Proteins
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RUNX1 protein, human
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Imatinib Mesylate
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KIT protein, human
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Proto-Oncogene Proteins c-kit