Alterations of the expression of TET2 and DNA 5-hmC predict poor prognosis in Myelodysplastic Neoplasms
Abstract Background Myelodysplastic Neoplasms (MDS) are clonal stem cell disorders characterized by ineffective hematopoiesis and progression to acute myeloid leukemia, myelodysplasia-related (AML-MR). A major mechanism of pathogenesis of MDS is the aberration of the epigenetic landscape of the hema...
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BMC
2023-10-01
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| Series: | BMC Cancer |
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| Online Access: | https://doi.org/10.1186/s12885-023-11449-2 |
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| author | Ashikh A. Seethy Karthikeyan Pethusamy Tushar Kushwaha Gaurav Kumar Joyeeta Talukdar Rekha Chaubey Udayakumar Dharmalingam Sundaram Manoranjan Mahapatra Renu Saxena Ruby Dhar Krishna K. Inampudi Subhradip Karmakar |
| author_facet | Ashikh A. Seethy Karthikeyan Pethusamy Tushar Kushwaha Gaurav Kumar Joyeeta Talukdar Rekha Chaubey Udayakumar Dharmalingam Sundaram Manoranjan Mahapatra Renu Saxena Ruby Dhar Krishna K. Inampudi Subhradip Karmakar |
| author_sort | Ashikh A. Seethy |
| collection | DOAJ |
| description | Abstract Background Myelodysplastic Neoplasms (MDS) are clonal stem cell disorders characterized by ineffective hematopoiesis and progression to acute myeloid leukemia, myelodysplasia-related (AML-MR). A major mechanism of pathogenesis of MDS is the aberration of the epigenetic landscape of the hematopoietic stem cells and/or progenitor cells, especially DNA cytosine methylation, and demethylation. Data on TET2, the predominant DNA demethylator of the hematopoietic system, is limited, particularly in the MDS patients from India, whose biology may differ since these patients present at a relatively younger age. We studied the expression and the variants of TET2 in Indian MDS and AML-MR patients and their effects on 5-hydroxymethyl cytosine (5-hmC, a product of TET2 catalysis) and on the prognosis of MDS patients. Results Of the 42 MDS patients, cytogenetics was available for 31 sub-categorized according to the Revised International Prognostic Scoring System (IPSS-R). Their age resembled that of the previous studies from India. Bone marrow nucleated cells (BMNCs) were also obtained from 13 patients with AML-MR, 26 patients with de-novo AML, and 11 subjects with morphologically normal bone marrow. The patients had a significantly lower TET2 expression which was more pronounced in AML-MR and the IPSS-R higher-risk MDS categories. The 5-hmC levels in higher-risk MDS and AML-MR correlated with TET2 expression, suggesting a possible mechanistic role in the loss of TET2 expression. The findings on TET2 and 5-hmC were also confirmed at the tissue level using immunohistochemistry. Pathogenic variants of TET2 were found in 7 of 24 patient samples (29%), spanning across the IPSS-R prognostic categories. One of the variants – H1778R – was found to affect local and global TET2 structure when studied using structural predictions and molecular dynamics simulations. Thus, it is plausible that some pathogenic variants in TET2 can compromise the structure of TET2 and hence in the formation of 5-hmC. Conclusions IPSS-R higher-risk MDS categories and AML-MR showed a reduction in TET2 expression, which was not apparent in lower-risk MDS. DNA 5-hmC levels followed a similar pattern. Overall, a decreased TET2 expression and a low DNA 5-hmC level are predictors of advanced disease and adverse outcome in MDS in the population studied, i.e., MDS patients from India. |
| first_indexed | 2024-03-11T15:14:49Z |
| format | Article |
| id | doaj.art-73ebd8e9f8494689b45070136816df16 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-03-11T15:14:49Z |
| publishDate | 2023-10-01 |
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| spelling | doaj.art-73ebd8e9f8494689b45070136816df162023-10-29T12:26:55ZengBMCBMC Cancer1471-24072023-10-0123111810.1186/s12885-023-11449-2Alterations of the expression of TET2 and DNA 5-hmC predict poor prognosis in Myelodysplastic NeoplasmsAshikh A. Seethy0Karthikeyan Pethusamy1Tushar Kushwaha2Gaurav Kumar3Joyeeta Talukdar4Rekha Chaubey5Udayakumar Dharmalingam Sundaram6Manoranjan Mahapatra7Renu Saxena8Ruby Dhar9Krishna K. Inampudi10Subhradip Karmakar11Department of Biochemistry, All India Institute of Medical SciencesDepartment of Biochemistry, All India Institute of Medical SciencesDepartment of Biophysics, All India Institute of Medical SciencesDepartment of Biochemistry, All India Institute of Medical SciencesDepartment of Biochemistry, All India Institute of Medical SciencesDepartment of Hematology, All India Institute of Medical SciencesDepartment of Hematology, All India Institute of Medical SciencesDepartment of Hematology, All India Institute of Medical SciencesDepartment of Hematology, All India Institute of Medical SciencesDepartment of Biochemistry, All India Institute of Medical SciencesDepartment of Biophysics, All India Institute of Medical SciencesDepartment of Biochemistry, All India Institute of Medical SciencesAbstract Background Myelodysplastic Neoplasms (MDS) are clonal stem cell disorders characterized by ineffective hematopoiesis and progression to acute myeloid leukemia, myelodysplasia-related (AML-MR). A major mechanism of pathogenesis of MDS is the aberration of the epigenetic landscape of the hematopoietic stem cells and/or progenitor cells, especially DNA cytosine methylation, and demethylation. Data on TET2, the predominant DNA demethylator of the hematopoietic system, is limited, particularly in the MDS patients from India, whose biology may differ since these patients present at a relatively younger age. We studied the expression and the variants of TET2 in Indian MDS and AML-MR patients and their effects on 5-hydroxymethyl cytosine (5-hmC, a product of TET2 catalysis) and on the prognosis of MDS patients. Results Of the 42 MDS patients, cytogenetics was available for 31 sub-categorized according to the Revised International Prognostic Scoring System (IPSS-R). Their age resembled that of the previous studies from India. Bone marrow nucleated cells (BMNCs) were also obtained from 13 patients with AML-MR, 26 patients with de-novo AML, and 11 subjects with morphologically normal bone marrow. The patients had a significantly lower TET2 expression which was more pronounced in AML-MR and the IPSS-R higher-risk MDS categories. The 5-hmC levels in higher-risk MDS and AML-MR correlated with TET2 expression, suggesting a possible mechanistic role in the loss of TET2 expression. The findings on TET2 and 5-hmC were also confirmed at the tissue level using immunohistochemistry. Pathogenic variants of TET2 were found in 7 of 24 patient samples (29%), spanning across the IPSS-R prognostic categories. One of the variants – H1778R – was found to affect local and global TET2 structure when studied using structural predictions and molecular dynamics simulations. Thus, it is plausible that some pathogenic variants in TET2 can compromise the structure of TET2 and hence in the formation of 5-hmC. Conclusions IPSS-R higher-risk MDS categories and AML-MR showed a reduction in TET2 expression, which was not apparent in lower-risk MDS. DNA 5-hmC levels followed a similar pattern. Overall, a decreased TET2 expression and a low DNA 5-hmC level are predictors of advanced disease and adverse outcome in MDS in the population studied, i.e., MDS patients from India.https://doi.org/10.1186/s12885-023-11449-2Myelodysplastic neoplasmsMyelodysplastic syndromeAML-myelodysplasia relatedAcute myeloid leukemia with myelodysplasia related changesEpigeneticsTET2 protein |
| spellingShingle | Ashikh A. Seethy Karthikeyan Pethusamy Tushar Kushwaha Gaurav Kumar Joyeeta Talukdar Rekha Chaubey Udayakumar Dharmalingam Sundaram Manoranjan Mahapatra Renu Saxena Ruby Dhar Krishna K. Inampudi Subhradip Karmakar Alterations of the expression of TET2 and DNA 5-hmC predict poor prognosis in Myelodysplastic Neoplasms BMC Cancer Myelodysplastic neoplasms Myelodysplastic syndrome AML-myelodysplasia related Acute myeloid leukemia with myelodysplasia related changes Epigenetics TET2 protein |
| title | Alterations of the expression of TET2 and DNA 5-hmC predict poor prognosis in Myelodysplastic Neoplasms |
| title_full | Alterations of the expression of TET2 and DNA 5-hmC predict poor prognosis in Myelodysplastic Neoplasms |
| title_fullStr | Alterations of the expression of TET2 and DNA 5-hmC predict poor prognosis in Myelodysplastic Neoplasms |
| title_full_unstemmed | Alterations of the expression of TET2 and DNA 5-hmC predict poor prognosis in Myelodysplastic Neoplasms |
| title_short | Alterations of the expression of TET2 and DNA 5-hmC predict poor prognosis in Myelodysplastic Neoplasms |
| title_sort | alterations of the expression of tet2 and dna 5 hmc predict poor prognosis in myelodysplastic neoplasms |
| topic | Myelodysplastic neoplasms Myelodysplastic syndrome AML-myelodysplasia related Acute myeloid leukemia with myelodysplasia related changes Epigenetics TET2 protein |
| url | https://doi.org/10.1186/s12885-023-11449-2 |
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