Imatinib independent aberrant methylation of NOV/CCN3 in chronic myelogenous leukemia patients: a mechanism upstream of BCR-ABL1 function?
Abstract Background The NOV gene product, CCN3, has been reported in a diverse range of tumors to serve as a negative growth regulator, while acting as a tumor suppressor in Chronic Myelogenous Leukemia (CML). However, the precise mechanism of its silencing in CML is poorly understood. In the curren...
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| Format: | Article |
| Language: | English |
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BMC
2019-04-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | http://link.springer.com/article/10.1186/s12964-019-0350-6 |
| _version_ | 1819133416464973824 |
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| author | Mousa Vatanmakanian Mahmood Tavallaie Shirin Ghadami |
| author_facet | Mousa Vatanmakanian Mahmood Tavallaie Shirin Ghadami |
| author_sort | Mousa Vatanmakanian |
| collection | DOAJ |
| description | Abstract Background The NOV gene product, CCN3, has been reported in a diverse range of tumors to serve as a negative growth regulator, while acting as a tumor suppressor in Chronic Myelogenous Leukemia (CML). However, the precise mechanism of its silencing in CML is poorly understood. In the current study, we aimed to query if the gene regulation of CCN3 is mediated by the promoter methylation in the patients with CML. In addition, to clarify whether the epigenetic silencing is affected by BCR-ABL1 inhibition, we assessed the methylation status in the patients at different time intervals following the tyrosine kinase inhibition using imatinib therapy, as the first-line treatment for this type of leukemia. Methods To address this issue, we applied bisulfite-sequencing technique as a high-resolution method to study the regulatory segment of the CCN3 gene. The results were analyzed in newly diagnosed CML patients as well as following imatinib therapy. We also evaluated the correlation of CCN3 promoter methylation with BCR-ABL1 levels. Results Our findings revealed that the methylation occurs frequently in the promoter region of CML patients showing a significant increase of the methylated percentage at the CpG sites compared to normal individuals. Interestingly, this hypermethylation was indicated to be independent of BCR-ABL1 titers in both groups, which might suggest a mechanism beyond the BCR-ABL1 function. Conclusion Despite suggesting that the CCN3 hypermethylation acts as a molecular mechanism independent of BCR-ABL1 function in CML patients, this scenario requires further validation by complementary experiments. In the case of acting upstream of BCR-ABL1 signaling, the methylation marker can provide early detection and a novel platform for targeted epigenetic modifiers for efficient treatment in imatinib resistant patients. |
| first_indexed | 2024-12-22T09:46:57Z |
| format | Article |
| id | doaj.art-e86ed908149649c9bf00e649a4977fb4 |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-12-22T09:46:57Z |
| publishDate | 2019-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-e86ed908149649c9bf00e649a4977fb42022-12-21T18:30:31ZengBMCCell Communication and Signaling1478-811X2019-04-0117111010.1186/s12964-019-0350-6Imatinib independent aberrant methylation of NOV/CCN3 in chronic myelogenous leukemia patients: a mechanism upstream of BCR-ABL1 function?Mousa Vatanmakanian0Mahmood Tavallaie1Shirin Ghadami2Human Genetics Research Center, Baqiyatallah University of Medical SciencesHuman Genetics Research Center, Baqiyatallah University of Medical SciencesHuman Genetics Research Center, Baqiyatallah University of Medical SciencesAbstract Background The NOV gene product, CCN3, has been reported in a diverse range of tumors to serve as a negative growth regulator, while acting as a tumor suppressor in Chronic Myelogenous Leukemia (CML). However, the precise mechanism of its silencing in CML is poorly understood. In the current study, we aimed to query if the gene regulation of CCN3 is mediated by the promoter methylation in the patients with CML. In addition, to clarify whether the epigenetic silencing is affected by BCR-ABL1 inhibition, we assessed the methylation status in the patients at different time intervals following the tyrosine kinase inhibition using imatinib therapy, as the first-line treatment for this type of leukemia. Methods To address this issue, we applied bisulfite-sequencing technique as a high-resolution method to study the regulatory segment of the CCN3 gene. The results were analyzed in newly diagnosed CML patients as well as following imatinib therapy. We also evaluated the correlation of CCN3 promoter methylation with BCR-ABL1 levels. Results Our findings revealed that the methylation occurs frequently in the promoter region of CML patients showing a significant increase of the methylated percentage at the CpG sites compared to normal individuals. Interestingly, this hypermethylation was indicated to be independent of BCR-ABL1 titers in both groups, which might suggest a mechanism beyond the BCR-ABL1 function. Conclusion Despite suggesting that the CCN3 hypermethylation acts as a molecular mechanism independent of BCR-ABL1 function in CML patients, this scenario requires further validation by complementary experiments. In the case of acting upstream of BCR-ABL1 signaling, the methylation marker can provide early detection and a novel platform for targeted epigenetic modifiers for efficient treatment in imatinib resistant patients.http://link.springer.com/article/10.1186/s12964-019-0350-6NOV/CCN3DNA methylationChronic myelogenous leukemia (CML)BCR-ABL1 |
| spellingShingle | Mousa Vatanmakanian Mahmood Tavallaie Shirin Ghadami Imatinib independent aberrant methylation of NOV/CCN3 in chronic myelogenous leukemia patients: a mechanism upstream of BCR-ABL1 function? Cell Communication and Signaling NOV/CCN3 DNA methylation Chronic myelogenous leukemia (CML) BCR-ABL1 |
| title | Imatinib independent aberrant methylation of NOV/CCN3 in chronic myelogenous leukemia patients: a mechanism upstream of BCR-ABL1 function? |
| title_full | Imatinib independent aberrant methylation of NOV/CCN3 in chronic myelogenous leukemia patients: a mechanism upstream of BCR-ABL1 function? |
| title_fullStr | Imatinib independent aberrant methylation of NOV/CCN3 in chronic myelogenous leukemia patients: a mechanism upstream of BCR-ABL1 function? |
| title_full_unstemmed | Imatinib independent aberrant methylation of NOV/CCN3 in chronic myelogenous leukemia patients: a mechanism upstream of BCR-ABL1 function? |
| title_short | Imatinib independent aberrant methylation of NOV/CCN3 in chronic myelogenous leukemia patients: a mechanism upstream of BCR-ABL1 function? |
| title_sort | imatinib independent aberrant methylation of nov ccn3 in chronic myelogenous leukemia patients a mechanism upstream of bcr abl1 function |
| topic | NOV/CCN3 DNA methylation Chronic myelogenous leukemia (CML) BCR-ABL1 |
| url | http://link.springer.com/article/10.1186/s12964-019-0350-6 |
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