DECODING THE ENTIRE DNA METHYLOME OF MANTLE CELL LYMPHOMA: NEW BIOLOGICAL AND CLINICAL INSIGHTS
(Abstract release date: 05/19/16)
EHA Library. Beekman R. 06/11/16; 135244; S488
Dr. Renée Beekman
Contributions
Contributions
Abstract
Abstract: S488
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:15 - 16:30
Location: Auditorium 1
Background
Mantle cell lymphoma (MCL) ranges from cases with rather indolent clinical behavior to very aggressive tumors with poor survival rates. Aggressive cases seem to be associated with low levels of somatic hypermutation (SHM) in the Immunoglobulin Heavy Chain (IGHV) gene, and de novo expression of SOX11. In contrast, indolent MCLs have high levels of IGHV somatic mutation and lack SOX11. Although many studies have focused on biological and clinical features of MCL, its methylome remains largely unknown. As recent studies have suggested a relationship between dynamic methylation during normal differentiation and neoplastic transformation, we hypothesized that a similar link exists in MCL.
Aims
We aimed to explore the DNA methylation landscape in MCL in light of the methylome in the entire B-cell lineage in order (i) to generate new insights into the biological and clinical aspects of MCL and (ii) to further understand the link between the dynamic methylation during normal differentiation and neoplastic transformation.
Methods
We generated genome-wide DNA methylation profiles of 86 MCL samples using the HumanMethylation450 BeadChip and we sequenced the DNA methylome of two representative MCLs by whole genome bisulfite sequencing (WGBS). As normal controls, we used samples (n=67 for BeadChip and n=12 for WGBS) from different B-cell subpopulations (n=10 for BeadChip and n=6 for WGBS).We applied a principal component analysis and consensus clustering to define epigenetic MCL subgroups and to determine their normal counterparts. Furthermore, to tackle the high individual epigenetic variation in MCL, we compared the DNA methylation profile of each individual MCL to a fixed reference point, the hematopoietic progenitor cells, and further analyzed the observed changes in the context of DNA methylation changes observed during B-cell differentiation.To understand the functional and clinical impact of DNA methylation changes we have linked our data with histone modification profiles (chIP-seq), the three-dimensional chromatin structure (4C-seq), the mutational landscape (whole genome/whole exome sequencing) and clinical data in MCL.
Results
First of all, we identified two epigenetic MCL subgroups that carry epigenetic imprints of pre- versus post-germinal center B cells. Secondly, we observed that the majority of individual DNA methylation changes in MCL also occur during normal B-cell differentiation and that pure tumor-specific changes are rare; most (89-99%) DNA methylation alterations in MCL are within or in close proximity to those regions showing dynamic methylation in normal B cells.Thirdly, several thousand differentially methylated regions in MCL show differential enhancer-associated histone modifications, including a region 650 Kb away from SOX11. In SOX11 expressing MCL cells, this distant region is hypomethylated and shows high contact frequencies with the SOX11 promoter in three-dimensional space, suggesting that we have identified a new regulatory element of SOX11 in MCL.Lastly, at the clinical level we observed that epigenetic and genetic changes co-evolve during MCL progression and that the magnitude of epigenetic changes is associated with overall survival of MCL patients.
Conclusion
Our results (i) provide new insights into the cellular origin, pathogenetic mechanisms and clinical behavior of MCL, (ii) show that pure tumor-specific DNA methylation changes in MCL are rare and (iii) highlight that differential methylation in cancer can target potential epigenetic drivers at distant regulatory elements of key oncogenes.
Session topic: Non-Hodgkin & Hodgkin lymphoma - Biology
Keyword(s): DNA methylation, Mantle cell lymphoma
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:15 - 16:30
Location: Auditorium 1
Background
Mantle cell lymphoma (MCL) ranges from cases with rather indolent clinical behavior to very aggressive tumors with poor survival rates. Aggressive cases seem to be associated with low levels of somatic hypermutation (SHM) in the Immunoglobulin Heavy Chain (IGHV) gene, and de novo expression of SOX11. In contrast, indolent MCLs have high levels of IGHV somatic mutation and lack SOX11. Although many studies have focused on biological and clinical features of MCL, its methylome remains largely unknown. As recent studies have suggested a relationship between dynamic methylation during normal differentiation and neoplastic transformation, we hypothesized that a similar link exists in MCL.
Aims
We aimed to explore the DNA methylation landscape in MCL in light of the methylome in the entire B-cell lineage in order (i) to generate new insights into the biological and clinical aspects of MCL and (ii) to further understand the link between the dynamic methylation during normal differentiation and neoplastic transformation.
Methods
We generated genome-wide DNA methylation profiles of 86 MCL samples using the HumanMethylation450 BeadChip and we sequenced the DNA methylome of two representative MCLs by whole genome bisulfite sequencing (WGBS). As normal controls, we used samples (n=67 for BeadChip and n=12 for WGBS) from different B-cell subpopulations (n=10 for BeadChip and n=6 for WGBS).We applied a principal component analysis and consensus clustering to define epigenetic MCL subgroups and to determine their normal counterparts. Furthermore, to tackle the high individual epigenetic variation in MCL, we compared the DNA methylation profile of each individual MCL to a fixed reference point, the hematopoietic progenitor cells, and further analyzed the observed changes in the context of DNA methylation changes observed during B-cell differentiation.To understand the functional and clinical impact of DNA methylation changes we have linked our data with histone modification profiles (chIP-seq), the three-dimensional chromatin structure (4C-seq), the mutational landscape (whole genome/whole exome sequencing) and clinical data in MCL.
Results
First of all, we identified two epigenetic MCL subgroups that carry epigenetic imprints of pre- versus post-germinal center B cells. Secondly, we observed that the majority of individual DNA methylation changes in MCL also occur during normal B-cell differentiation and that pure tumor-specific changes are rare; most (89-99%) DNA methylation alterations in MCL are within or in close proximity to those regions showing dynamic methylation in normal B cells.Thirdly, several thousand differentially methylated regions in MCL show differential enhancer-associated histone modifications, including a region 650 Kb away from SOX11. In SOX11 expressing MCL cells, this distant region is hypomethylated and shows high contact frequencies with the SOX11 promoter in three-dimensional space, suggesting that we have identified a new regulatory element of SOX11 in MCL.Lastly, at the clinical level we observed that epigenetic and genetic changes co-evolve during MCL progression and that the magnitude of epigenetic changes is associated with overall survival of MCL patients.
Conclusion
Our results (i) provide new insights into the cellular origin, pathogenetic mechanisms and clinical behavior of MCL, (ii) show that pure tumor-specific DNA methylation changes in MCL are rare and (iii) highlight that differential methylation in cancer can target potential epigenetic drivers at distant regulatory elements of key oncogenes.
Session topic: Non-Hodgkin & Hodgkin lymphoma - Biology
Keyword(s): DNA methylation, Mantle cell lymphoma
Abstract: S488
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:15 - 16:30
Location: Auditorium 1
Background
Mantle cell lymphoma (MCL) ranges from cases with rather indolent clinical behavior to very aggressive tumors with poor survival rates. Aggressive cases seem to be associated with low levels of somatic hypermutation (SHM) in the Immunoglobulin Heavy Chain (IGHV) gene, and de novo expression of SOX11. In contrast, indolent MCLs have high levels of IGHV somatic mutation and lack SOX11. Although many studies have focused on biological and clinical features of MCL, its methylome remains largely unknown. As recent studies have suggested a relationship between dynamic methylation during normal differentiation and neoplastic transformation, we hypothesized that a similar link exists in MCL.
Aims
We aimed to explore the DNA methylation landscape in MCL in light of the methylome in the entire B-cell lineage in order (i) to generate new insights into the biological and clinical aspects of MCL and (ii) to further understand the link between the dynamic methylation during normal differentiation and neoplastic transformation.
Methods
We generated genome-wide DNA methylation profiles of 86 MCL samples using the HumanMethylation450 BeadChip and we sequenced the DNA methylome of two representative MCLs by whole genome bisulfite sequencing (WGBS). As normal controls, we used samples (n=67 for BeadChip and n=12 for WGBS) from different B-cell subpopulations (n=10 for BeadChip and n=6 for WGBS).We applied a principal component analysis and consensus clustering to define epigenetic MCL subgroups and to determine their normal counterparts. Furthermore, to tackle the high individual epigenetic variation in MCL, we compared the DNA methylation profile of each individual MCL to a fixed reference point, the hematopoietic progenitor cells, and further analyzed the observed changes in the context of DNA methylation changes observed during B-cell differentiation.To understand the functional and clinical impact of DNA methylation changes we have linked our data with histone modification profiles (chIP-seq), the three-dimensional chromatin structure (4C-seq), the mutational landscape (whole genome/whole exome sequencing) and clinical data in MCL.
Results
First of all, we identified two epigenetic MCL subgroups that carry epigenetic imprints of pre- versus post-germinal center B cells. Secondly, we observed that the majority of individual DNA methylation changes in MCL also occur during normal B-cell differentiation and that pure tumor-specific changes are rare; most (89-99%) DNA methylation alterations in MCL are within or in close proximity to those regions showing dynamic methylation in normal B cells.Thirdly, several thousand differentially methylated regions in MCL show differential enhancer-associated histone modifications, including a region 650 Kb away from SOX11. In SOX11 expressing MCL cells, this distant region is hypomethylated and shows high contact frequencies with the SOX11 promoter in three-dimensional space, suggesting that we have identified a new regulatory element of SOX11 in MCL.Lastly, at the clinical level we observed that epigenetic and genetic changes co-evolve during MCL progression and that the magnitude of epigenetic changes is associated with overall survival of MCL patients.
Conclusion
Our results (i) provide new insights into the cellular origin, pathogenetic mechanisms and clinical behavior of MCL, (ii) show that pure tumor-specific DNA methylation changes in MCL are rare and (iii) highlight that differential methylation in cancer can target potential epigenetic drivers at distant regulatory elements of key oncogenes.
Session topic: Non-Hodgkin & Hodgkin lymphoma - Biology
Keyword(s): DNA methylation, Mantle cell lymphoma
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:15 - 16:30
Location: Auditorium 1
Background
Mantle cell lymphoma (MCL) ranges from cases with rather indolent clinical behavior to very aggressive tumors with poor survival rates. Aggressive cases seem to be associated with low levels of somatic hypermutation (SHM) in the Immunoglobulin Heavy Chain (IGHV) gene, and de novo expression of SOX11. In contrast, indolent MCLs have high levels of IGHV somatic mutation and lack SOX11. Although many studies have focused on biological and clinical features of MCL, its methylome remains largely unknown. As recent studies have suggested a relationship between dynamic methylation during normal differentiation and neoplastic transformation, we hypothesized that a similar link exists in MCL.
Aims
We aimed to explore the DNA methylation landscape in MCL in light of the methylome in the entire B-cell lineage in order (i) to generate new insights into the biological and clinical aspects of MCL and (ii) to further understand the link between the dynamic methylation during normal differentiation and neoplastic transformation.
Methods
We generated genome-wide DNA methylation profiles of 86 MCL samples using the HumanMethylation450 BeadChip and we sequenced the DNA methylome of two representative MCLs by whole genome bisulfite sequencing (WGBS). As normal controls, we used samples (n=67 for BeadChip and n=12 for WGBS) from different B-cell subpopulations (n=10 for BeadChip and n=6 for WGBS).We applied a principal component analysis and consensus clustering to define epigenetic MCL subgroups and to determine their normal counterparts. Furthermore, to tackle the high individual epigenetic variation in MCL, we compared the DNA methylation profile of each individual MCL to a fixed reference point, the hematopoietic progenitor cells, and further analyzed the observed changes in the context of DNA methylation changes observed during B-cell differentiation.To understand the functional and clinical impact of DNA methylation changes we have linked our data with histone modification profiles (chIP-seq), the three-dimensional chromatin structure (4C-seq), the mutational landscape (whole genome/whole exome sequencing) and clinical data in MCL.
Results
First of all, we identified two epigenetic MCL subgroups that carry epigenetic imprints of pre- versus post-germinal center B cells. Secondly, we observed that the majority of individual DNA methylation changes in MCL also occur during normal B-cell differentiation and that pure tumor-specific changes are rare; most (89-99%) DNA methylation alterations in MCL are within or in close proximity to those regions showing dynamic methylation in normal B cells.Thirdly, several thousand differentially methylated regions in MCL show differential enhancer-associated histone modifications, including a region 650 Kb away from SOX11. In SOX11 expressing MCL cells, this distant region is hypomethylated and shows high contact frequencies with the SOX11 promoter in three-dimensional space, suggesting that we have identified a new regulatory element of SOX11 in MCL.Lastly, at the clinical level we observed that epigenetic and genetic changes co-evolve during MCL progression and that the magnitude of epigenetic changes is associated with overall survival of MCL patients.
Conclusion
Our results (i) provide new insights into the cellular origin, pathogenetic mechanisms and clinical behavior of MCL, (ii) show that pure tumor-specific DNA methylation changes in MCL are rare and (iii) highlight that differential methylation in cancer can target potential epigenetic drivers at distant regulatory elements of key oncogenes.
Session topic: Non-Hodgkin & Hodgkin lymphoma - Biology
Keyword(s): DNA methylation, Mantle cell lymphoma
{{ help_message }}
{{filter}}