Hypermethylation of the spleen tyrosine kinase promoter in T-lineage acute lymphoblastic leukemia
| Autor: | Brian Juran, Nicole Burkhardt, Faith M Uckun, Heather E Tibbles, Patricia A. Goodman |
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| Rok vydání: | 2003 |
| Předmět: |
Cancer Research
Molecular Sequence Data Bisulfite sequencing Syk Bone Marrow Cells In Vitro Techniques Biology Jurkat cells hemic and lymphatic diseases Acute lymphocytic leukemia Genetics medicine Humans Syk Kinase Promoter Regions Genetic Molecular Biology Enzyme Precursors Base Sequence Intracellular Signaling Peptides and Proteins hemic and immune systems Sequence Analysis DNA Methylation DNA Methylation Precursor Cell Lymphoblastic Leukemia-Lymphoma Protein-Tyrosine Kinases medicine.disease Molecular biology Leukemia CpG site DNA methylation Cancer research CpG Islands Spleen |
| Zdroj: | Oncogene. 22:2504-2514 |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | Sequence analysis of the noncoding first exon (exon 1) of the Syk gene demonstrated the presence of a previously cloned CpG island (GenBank #Z 65706). Transient transfection analysis in Daudi cells demonstrated promoter activity (18-fold increase over parental luciferase plasmid) for a 348 bp BstXI-BsrBI fragment containing this island. This region exhibits a high GC content (approximately 75%), contains several SP1 binding sites and a potential initiator sequence, but lacks a strong TATA consensus. Bisulfite sequencing and methylation-specific PCR (MSP) of this region demonstrated that the Syk promoter CpG island was largely unmethylated in B-lineage leukemia cell lines, control peripheral blood cells, human thymocytes and CD3(+) T lymphocytes. However, dense methylation was seen in four T-lineage leukemia cell lines, Jurkat, H9, Molt 3 and HUT 78. MSP screening of leukemia cells from six T-lineage acute lymphoblastic leukemia (ALL) patients demonstrated methylation of the Syk promoter CpG island in one T-lineage ALL patient. Promoter methylation was correlated with reduced to absent expression of Syk mRNA and SYK protein in the T-lineage leukemia cell lines. Treatment of the leukemia lines Ha and Molt 3, with the methylation inhibitor, 5-aza-2'-deoxycytidine (5-aza-CdR) resulted in increased Syk mRNA expression. The presence of a methylated promoter sequence in these T-lineage leukemia cell lines and in one T-lineage patient suggests a potential role for SYK as a tumor suppressor in T-ALL. |
| Databáze: | OpenAIRE |
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