Abstract
Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of acute myeloid leukemia (AML) and poor survival rate. Here, we report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and is inhibited by small molecule compounds, including disulfiram that directly targets the PHD finger of PHF23 (PHF23PHD). Our data support a critical role for the PHD fingers of NUP98-PHF23, and related NUP98-KDM5A and NUP98-BPTF fusions in driving leukemogenesis, and demonstrate that blocking this interaction in NUP98-PHF23 expressing AML cells leads to cell death through necrotic and late apoptosis pathways. An overlap of NUP98-KDM5A oncoprotein binding sites and H3K4me3-positive loci at the Hoxa/b gene clusters and Meis1 in ChIP-seq, together with NMR analysis of the H3K4me3-binding sites of the PHD fingers from PHF23, KDM5A and BPTF, suggests a common PHD finger-dependent mechanism that promotes leukemogenesis by this type of NUP98 fusions. Our findings highlight the direct correlation between the abilities of NUP98-PHD finger fusion chimeras to associate with H3K4me3-enriched chromatin and leukemic transformation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Disease
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Antigens, Nuclear / genetics
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Antigens, Nuclear / metabolism
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Chromatin / genetics
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Chromatin / metabolism*
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Disulfiram / pharmacology
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Histones / metabolism
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Humans
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Leukemia, Myeloid / genetics
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Leukemia, Myeloid / metabolism*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Nuclear Pore Complex Proteins / genetics
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Nuclear Pore Complex Proteins / metabolism*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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PHD Zinc Fingers / genetics
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Protein Processing, Post-Translational / drug effects
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Retinoblastoma-Binding Protein 2 / genetics
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Retinoblastoma-Binding Protein 2 / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Translocation, Genetic / drug effects
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Translocation, Genetic / genetics
Substances
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Antigens, Nuclear
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Chromatin
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Histones
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Homeodomain Proteins
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Nerve Tissue Proteins
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Nuclear Pore Complex Proteins
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Nup98 protein, human
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Oncogene Proteins, Fusion
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PHF23 protein, human
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Transcription Factors
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fetal Alzheimer antigen
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histone H3 trimethyl Lys4
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KDM5A protein, human
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Retinoblastoma-Binding Protein 2
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Disulfiram