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Open Access Green as soon as Postprint is submitted to ZB.
Aberrant ZNF423 impedes B cell differentiation and is linked to adverse outcome of ETV6-RUNX1 negative B precursor acute lymphoblastic leukemia.
J. Exp. Med. 210, 2289-2304 (2013)
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 ZNF423 alpha and a novel ZNF423 beta-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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Zinc-finger Protein ; Dna Methylation ; Gene-expression ; Target ; Identification ; Neuroblastoma ; Zfp423/oaz ; Marker ; Cancer ; Motif
ISSN (print) / ISBN
0022-1007
e-ISSN
1540-9538
Journal
Journal of Experimental Medicine
Quellenangaben
Volume: 210,
Issue: 11,
Pages: 2289-2304
Publisher
Rockefeller University Press
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Molecular Immunology (IMI)