Epigenetic Inactivation of Notch-Hes Pathway in Human B-Cell Acute Lymphoblastic Leukemia
Open Access
- 26 April 2013
- journal article
- biology
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (4), e61807
- https://doi.org/10.1371/journal.pone.0061807
Abstract
The Notch pathway can have both oncogenic and tumor suppressor roles, depending on cell context. For example, Notch signaling promotes T cell differentiation and is leukemogenic in T cells, whereas it inhibits early B cell differentiation and acts as a tumor suppressor in B cell leukemia where it induces growth arrest and apoptosis. The regulatory mechanisms that contribute to these opposing roles are not understood. Aberrant promoter DNA methylation and histone modifications are associated with silencing of tumor suppressor genes and have been implicated in leukemogenesis. Using methylated CpG island amplification (MCA)/DNA promoter microarray, we identified Notch3 and Hes5 as hypermethylated in human B cell acute lymphoblastic leukemia (ALL). We investigated the methylation status of other Notch pathway genes by bisulfite pyrosequencing. Notch3, JAG1, Hes2, Hes4 and Hes5 were frequently hypermethylated in B leukemia cell lines and primary B-ALL, in contrast to T-ALL cell lines and patient samples. Aberrant methylation of Notch3 and Hes5 in B-ALL was associated with gene silencing and was accompanied by decrease of H3K4 trimethylation and H3K9 acetylation and gain of H3K9 trimethylation and H3K27 trimethylation. 5-aza-2′-deoxycytidine treatment restored Hes5 expression and decreased promoter hypermethylation in most leukemia cell lines and primary B-ALL samples. Restoration of Hes5 expression by lentiviral transduction resulted in growth arrest and apoptosis in Hes5 negative B-ALL cells but not in Hes5 expressing T-ALL cells. These data suggest that epigenetic modifications are implicated in silencing of tumor suppressor of Notch/Hes pathway in B-ALL.Keywords
This publication has 25 references indexed in Scilit:
- Notch tumor suppressor functionOncogene, 2008
- Stem cell–specific epigenetic priming and B cell–specific transcriptional activation at the mouse Cd19 locusBlood, 2008
- Jagged-1 and Notch3 Juxtacrine Loop Regulates Ovarian Tumor Growth and AdhesionCancer Research, 2008
- Notch Signaling in Leukemias and LymphomasCurrent Molecular Medicine, 2008
- Integrative genomic analyses on HES/HEY family: Notch-independent HES1, HES3 transcription in undifferentiated ES cells, and Notch-dependent HES1, HES5, HEY1, HEY2, HEYL transcription in fetal tissues, adult tissues, or cancerInternational Journal of Oncology, 2007
- Recent insights into the role of Notch signaling in tumorigenesisBlood, 2006
- Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic LeukemiaScience, 2004
- Notch signalling in B cellsSeminars in Cell & Developmental Biology, 2003
- Expression of notch receptors, notch ligands, and fringe genes in hematopoiesisExperimental Hematology, 2000
- TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasmsCell, 1991