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TWIST2 Demonstrates Differential Methylation in Immunoglobulin Variable Heavy Chain Mutated and Unmutated Chronic Lymphocytic Leukemia
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| Zeitschriftentitel: | Journal of Clinical Oncology |
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| Personen und Körperschaften: | , , , , , , , , , , |
| In: | Journal of Clinical Oncology, 23, 2005, 17, S. 3877-3885 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society of Clinical Oncology (ASCO)
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| Schlagwörter: |
| Zusammenfassung: | <jats:sec><jats:title>Purpose</jats:title><jats:p> Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease for which natural history can be predicted based on the presence or absence of immunoglobulin (Ig) variable heavy chain (V<jats:sub>H</jats:sub>) gene mutations. Herein we report selective epigenetic silencing of the transcription factor TWIST2 (DERMO1) in Ig V<jats:sub>H</jats:sub> mutated CLL and describe a semiquantitative assay to study promoter methylation of this gene in primary tumor cells. </jats:p></jats:sec><jats:sec><jats:title>Materials and Methods</jats:title><jats:p> TWIST2 promoter methylation was identified by restriction landmark genome scanning. Southern blot (SB), bisulfite sequencing, and combined bisulfite restriction analysis (COBRA), and quantitative SB-COBRA was performed to study methylation of the TWIST2 promoter. Reverse transcription polymerase chain reaction assays were used to study TWIST2 expression in CLL cells. </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p> Following identification and confirmation of TWIST2 methylation in CLL patients, we demonstrated that expression of this transcription factor is related to the degree of promoter methylation. Expression of TWIST2 in a CLL cell line in which the promoter is methylated was increased following decitabine treatment. We next studied 53 patients by COBRA and demonstrated that 72% of patient samples with mutated Ig V<jats:sub>H</jats:sub> show TWIST2 methylation, while only 16% of patient samples with unmutated Ig V<jats:sub>H</jats:sub> were methylated (P < .001). In a subset of patients, methylation of TWIST2 correlated with mRNA expression. </jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p> TWIST2 is differentially methylated in CLL cells relative to Ig V<jats:sub>H</jats:sub> mutational status and can be quantitatively monitored by SB-COBRA. Based on the known role of TWIST2 in silencing p53 function in other malignancies, future studies should focus on the role of TWIST2 in CLL and related lymphoproliferative diseases. </jats:p></jats:sec> |
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| Umfang: | 3877-3885 |
| ISSN: |
1527-7755
0732-183X |
| DOI: | 10.1200/jco.2005.02.196 |