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

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.

DOI: 10.1084/jem.20130497

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@inproceedings{Harder2013AberrantZI, title={Aberrant ZNF423 impedes B cell differentiation and is linked to adverse outcome of ETV6-RUNX1 negative B precursor acute lymphoblastic leukemia}, author={Lena Harder and Georg Eschenburg and Antonia T L Zech and Neele Kriebitzsch and Benjamin Otto and Thomas Streichert and Anna-Sophie Behlich and Kevin Dierck and Bine Klingler and Arne Hansen and Martin Stanulla and Martin Zimmermann and Elisabeth Kremmer and Carol Stocking and Martin A Horstmann}, booktitle={The Journal of experimental medicine}, year={2013} }