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Research article
Sameer Ahmad Guru
Maulana Azad Medical College
Corresponding Author
ORCiD: https://orcid.org/0000-0003-0447-0176
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Background: There is strong evidence that disease progression, drug response and overall clinical outcome of CML disease are not only decided by BCR/ABL1 oncoprotein but depend on accumulation of additional genetic and epigenetic aberrations. DNA hydroxymethylation is implicated in the development of variety of diseases. DNA hydroxymethylation in gene promoters plays an important role in disease progression, drug response and clinical outcome of various diseases. Therefore in this study, we aimed to explore the role of aberrant hydroxymethylation in promoter regions of different tumor suppressor genes in relation to CML disease progression, response to imatinib therapy and clinical outcome.
We recruited 150 CML patients at different clinical stages of the disease. Patients were followed up for 48 months and haematological/molecular responses were analysed. Haematological response was analysed by peripheral blood smear. BCR/ABL1 specific TaqMan probe based qRT-PCR was used for assessing the molecular response of CML patients on imatinib therapy. Promoter hydroxymethylation of the genes was characterized using MS-PCR.
Results: We observed that promoter hydroxymethylation of cell cycle regulating and apoptosis related genes characterize advanced CML disease and poor imatinib respondents. Although, cytokine signalling (SOCS1) gene was hypermethylated in advanced stages of CML and accumulated in patients with poor imatinib response, but the differences were not statistically significant. Moreover, we found hypermethylation of cell cycle regulating genes (p14ARF, RASSF1 and p16INK4A) and cytokine signalling gene (SOCS1) significantly associated with poor overall survival of CML patients on imatinib therapy. The results of this study are in agreement of the role of aberrant DNA methylation of different tumor suppressor genes as potential biomarkers of CML disease progression, poor imatinib response and overall clinical outcome.
Conclusion: In this study, we report that promoter hydroxymethylation of cell cycle and apoptosis related genes is a characteristic feature of CML disease progression, defines poor imatinib respondents and poor overall survival of CML patients to imatinib therapy.
Keywords
Chronic Myeloid Leukaemia, Imatinib, Epigenetics, Promoter hypermethylation, Cell cycle and apoptosis related genes.
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A new preprint design is coming!
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This preprint is under consideration at BMC Cancer. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Sameer Ahmad Guru
Maulana Azad Medical College
Corresponding Author
ORCiD: https://orcid.org/0000-0003-0447-0176
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 15 Feb, 2021
No community comments so far
Reviewer #1 agreed
On 30 Dec, 2020
Review #1 received
Received 30 Dec, 2020
Reviewers invited
Invitations sent on 25 Dec, 2020
Editor assigned
On 17 Dec, 2020
Submission checks complete
On 17 Dec, 2020
Editor invited
On 17 Dec, 2020
First submitted
On 26 Nov, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: There is strong evidence that disease progression, drug response and overall clinical outcome of CML disease are not only decided by BCR/ABL1 oncoprotein but depend on accumulation of additional genetic and epigenetic aberrations. DNA hydroxymethylation is implicated in the development of variety of diseases. DNA hydroxymethylation in gene promoters plays an important role in disease progression, drug response and clinical outcome of various diseases. Therefore in this study, we aimed to explore the role of aberrant hydroxymethylation in promoter regions of different tumor suppressor genes in relation to CML disease progression, response to imatinib therapy and clinical outcome.
We recruited 150 CML patients at different clinical stages of the disease. Patients were followed up for 48 months and haematological/molecular responses were analysed. Haematological response was analysed by peripheral blood smear. BCR/ABL1 specific TaqMan probe based qRT-PCR was used for assessing the molecular response of CML patients on imatinib therapy. Promoter hydroxymethylation of the genes was characterized using MS-PCR.
Results: We observed that promoter hydroxymethylation of cell cycle regulating and apoptosis related genes characterize advanced CML disease and poor imatinib respondents. Although, cytokine signalling (SOCS1) gene was hypermethylated in advanced stages of CML and accumulated in patients with poor imatinib response, but the differences were not statistically significant. Moreover, we found hypermethylation of cell cycle regulating genes (p14ARF, RASSF1 and p16INK4A) and cytokine signalling gene (SOCS1) significantly associated with poor overall survival of CML patients on imatinib therapy. The results of this study are in agreement of the role of aberrant DNA methylation of different tumor suppressor genes as potential biomarkers of CML disease progression, poor imatinib response and overall clinical outcome.
Conclusion: In this study, we report that promoter hydroxymethylation of cell cycle and apoptosis related genes is a characteristic feature of CML disease progression, defines poor imatinib respondents and poor overall survival of CML patients to imatinib therapy.
Figure 1
Figure 2
Figure 3
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