title: Epigenetic inactivation of Notch-Hes pathway in human B-cell acute lymphoblastic leukemia.
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.
authors: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors: Shao-Qing
authors: SQ
authors: Kuang
authors: Zhihong
authors: Z
authors: Fang
authors: Patrick A
authors: PA
authors: Zweidler-McKay
authors: Hui
authors: H
authors: Yang
authors: Yue
authors: Y
authors: Wei
authors: Emilio A
authors: EA
authors: Gonzalez-Cervantes
authors: Yanis
authors: Y
authors: Boumber
authors: Guillermo
authors: G
authors: Garcia-Manero
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D001773:Blood Cells / Q000187:drug effects / Q000378:metabolism; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D000077209:Decitabine; D044127:Epigenesis, Genetic / Q000187:drug effects; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D015448:Leukemia, B-Cell / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000235:genetics* / Q000473:pathology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D001374:Azacitidine; D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D000077209:Decitabine; D006657:Histones; D006877:Hydroxamic Acids; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D012097:Repressor Proteins; D000072099:Serrate-Jagged Proteins; D000077337:Vorinostat; C000606273:JAG1 protein, human; C499374:NOTCH3 protein, human; C077478:HES5 protein, human
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