Abstract
Differentiation arrest is a hallmark of acute leukemia. Genomic alterations in B cell differentiation factors such as PAX5, IKZF1, and EBF-1 have been identified in more than half of all cases of childhood B precursor acute lymphoblastic leukemia (ALL). Here, we describe a perturbed epigenetic and transcriptional regulation of ZNF423 in ALL as a novel mechanism interfering with B cell differentiation. Hypomethylation of ZNF423 regulatory sequences and BMP2 signaling result in transactivation of ZNF423α and a novel ZNF423β-isoform encoding a nucleosome remodeling and histone deacetylase complex-interacting domain. Aberrant ZNF423 inhibits the transactivation of EBF-1 target genes and leads to B cell maturation arrest in vivo. Importantly, ZNF423 expression is associated with poor outcome of ETV6-RUNX1-negative B precursor ALL patients. Our work demonstrates that ALL is more than a genetic disease and that epigenetics may uncover novel mechanisms of disease with prognostic implications.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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B-Lymphocytes / metabolism
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B-Lymphocytes / pathology*
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Bone Morphogenetic Protein 2 / metabolism
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Cell Differentiation* / genetics
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Cell Lineage / genetics
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Core Binding Factor Alpha 2 Subunit / metabolism*
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DNA Methylation / genetics
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Disease-Free Survival
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Gene Expression Profiling
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Gene Expression Regulation, Leukemic
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Hematopoietic Stem Cells / metabolism
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Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism
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Mice
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Oncogene Proteins, Fusion / metabolism*
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology*
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Prognosis
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Protein Binding / genetics
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Protein Isoforms / metabolism
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Protein Structure, Tertiary
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Proteins
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Signal Transduction / genetics
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Smad Proteins / metabolism
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Trans-Activators / genetics
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Transcriptional Activation / genetics
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Up-Regulation / genetics
Substances
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BMP2 protein, human
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Bone Morphogenetic Protein 2
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Core Binding Factor Alpha 2 Subunit
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DNA-Binding Proteins
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EBF1 protein, human
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Neoplasm Proteins
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Oncogene Proteins, Fusion
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Protein Isoforms
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Proteins
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Smad Proteins
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TEL-AML1 fusion protein
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Trans-Activators
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ornithine decarboxylase antizyme
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Mi-2 Nucleosome Remodeling and Deacetylase Complex