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24081948
Aberrant ZNF423 impedes B cell differentiation and is linked to adverse outcome of ETV6-RUNX1 negative B precursor acute lymphoblastic leukemia.

J Exp Med, 2013/10/21;210(11):2289-304.

Harder L[1], Eschenburg G, Zech A, Kriebitzsch N, Otto B, Streichert T, Behlich AS, Dierck K, Klingler B, Hansen A, Stanulla M, Zimmermann M, Kremmer E, Stocking C, Horstmann MA

Affiliations

PMID: 24081948DOI: 10.1084/jem.20130497

Impact factor: 17.579

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.
MeSH terms
Animals; B-Lymphocytes; Bone Morphogenetic Protein 2; Cell Differentiation; Cell Lineage; Core Binding Factor Alpha 2 Subunit; DNA Methylation; DNA-Binding Proteins; Disease-Free Survival; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Hematopoietic Stem Cells; Mi-2 Nucleosome Remodeling and Deacetylase Complex; Mice; Neoplasm Proteins; Oncogene Proteins, Fusion; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Protein Binding; Protein Isoforms; Protein Structure, Tertiary; Proteins; Signal Transduction; Smad Proteins; Trans-Activators; Transcriptional Activation; Up-Regulation
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