The Experts below are selected from a list of 87 Experts worldwide ranked by ideXlab platform
Colin Flinders - One of the best experts on this subject based on the ideXlab platform.
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Epigenetic changes mediated by polycomb repressive complex 2 and E2a are associated with Drug resistance in a mouse model of lymphoma
Genome Medicine, 2016Co-Authors: Colin Flinders, Larry Lam, Liudmilla Rubbi, Roberto Ferrari, Sorel Fitz-gibbon, Pao-yang Chen, Heather R. Christofk, Michael Thompson, David Agus, Daniel RudermanAbstract:Background The genetic origins of chemotherapy resistance are well established; however, the role of epigenetics in Drug resistance is less well understood. To investigate mechanisms of Drug resistance, we performed systematic genetic, epigenetic, and transcriptomic analyses of an alkylating agent-sensitive murine lymphoma cell line and a series of resistant lines derived by Drug Dose Escalation. Methods Dose Escalation of the alkylating agent mafosfamide was used to create a series of increasingly Drug-resistant mouse Burkitt’s lymphoma cell lines. Whole genome sequencing, DNA microarrays, reduced representation bisulfite sequencing, and chromatin immunoprecipitation sequencing were used to identify alterations in DNA sequence, mRNA expression, CpG methylation, and H3K27me3 occupancy, respectively, that were associated with increased resistance. Results Our data suggest that acquired resistance cannot be explained by genetic alterations. Based on integration of transcriptional profiles with transcription factor binding data, we hypothesize that resistance is driven by epigenetic plasticity. We observed that the resistant cells had H3K27me3 and DNA methylation profiles distinct from those of the parental lines. Moreover, we observed DNA methylation changes in the promoters of genes regulated by E2a and members of the polycomb repressor complex 2 (PRC2) and differentially expressed genes were enriched for targets of E2a. The integrative analysis considering H3K27me3 further supported a role for PRC2 in mediating resistance. By integrating our results with data from the Immunological Genome Project (Immgen.org), we showed that these transcriptional changes track the B-cell maturation axis. Conclusions Our data suggest a novel mechanism of Drug resistance in which E2a and PRC2 drive changes in the B-cell epigenome; these alterations attenuate alkylating agent treatment-induced apoptosis.
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Epigenetic changes mediated by polycomb repressive complex 2 and E2a are associated with Drug resistance in a mouse model of lymphoma
Genome medicine, 2016Co-Authors: Colin Flinders, Larry Lam, Liudmilla Rubbi, Roberto Ferrari, Sorel Fitz-gibbon, Pao-yang Chen, Michael C. Thompson, Heather R. Christofk, David B. Agus, Daniel L. RudermanAbstract:Background The genetic origins of chemotherapy resistance are well established; however, the role of epigenetics in Drug resistance is less well understood. To investigate mechanisms of Drug resistance, we performed systematic genetic, epigenetic, and transcriptomic analyses of an alkylating agent-sensitive murine lymphoma cell line and a series of resistant lines derived by Drug Dose Escalation.
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Mulit-omic Analysis of B-Cell Lymphoma Reveals Novel Mechanisms of hemotherapeutic Drug Resistance
2015Co-Authors: Colin FlindersAbstract:The genetic origins of chemotherapy resistance are well established, however the role of the epigenome and post-transcriptional regulation in Drug resistance is less well understood. To investigate mechanisms of Drug resistance we performed a systematic genetic, epigenetic, transcriptomic and proteomic analysis of a mafosfamide sensitive and resistant murine lymphoma cell line, along with a series of resistant lines derived by Drug Dose Escalation. Our data suggest that acquired resistance could not be explained by genetic alterations. By integrating our transcriptional profiles with transcription factor binding data we hypothesize that the resistance was associated with changes in the activity of the polycomb repressive complex (Prc2) as well as the transcription factor E2a. We verified that the resistant cells had distinct H3K27me3 and DNA methylation profiles, compared to the parental lines, and differentially expressed genes were enriched for targets of E2a. In addition, the resistant lines appear to de-differentiate to a less mature state along the B cell maturation axis. Overall, we propose that resistant lines are transformed by an E2a and Pcr2 driven cellular program that leads to a less mature B cell state in which the apoptotic cascade induced by mafosfamide treatment is attenuated. Furthermore, combined transcriptomic and proteomic data analysis elucidated mechanisms of resistance involving the ubiquitination activating enzyme Uba1 which were not revealed by analysis of either transcriptomic or proteomic data alone.
Daniel Ruderman - One of the best experts on this subject based on the ideXlab platform.
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Epigenetic changes mediated by polycomb repressive complex 2 and E2a are associated with Drug resistance in a mouse model of lymphoma
Genome Medicine, 2016Co-Authors: Colin Flinders, Larry Lam, Liudmilla Rubbi, Roberto Ferrari, Sorel Fitz-gibbon, Pao-yang Chen, Heather R. Christofk, Michael Thompson, David Agus, Daniel RudermanAbstract:Background The genetic origins of chemotherapy resistance are well established; however, the role of epigenetics in Drug resistance is less well understood. To investigate mechanisms of Drug resistance, we performed systematic genetic, epigenetic, and transcriptomic analyses of an alkylating agent-sensitive murine lymphoma cell line and a series of resistant lines derived by Drug Dose Escalation. Methods Dose Escalation of the alkylating agent mafosfamide was used to create a series of increasingly Drug-resistant mouse Burkitt’s lymphoma cell lines. Whole genome sequencing, DNA microarrays, reduced representation bisulfite sequencing, and chromatin immunoprecipitation sequencing were used to identify alterations in DNA sequence, mRNA expression, CpG methylation, and H3K27me3 occupancy, respectively, that were associated with increased resistance. Results Our data suggest that acquired resistance cannot be explained by genetic alterations. Based on integration of transcriptional profiles with transcription factor binding data, we hypothesize that resistance is driven by epigenetic plasticity. We observed that the resistant cells had H3K27me3 and DNA methylation profiles distinct from those of the parental lines. Moreover, we observed DNA methylation changes in the promoters of genes regulated by E2a and members of the polycomb repressor complex 2 (PRC2) and differentially expressed genes were enriched for targets of E2a. The integrative analysis considering H3K27me3 further supported a role for PRC2 in mediating resistance. By integrating our results with data from the Immunological Genome Project (Immgen.org), we showed that these transcriptional changes track the B-cell maturation axis. Conclusions Our data suggest a novel mechanism of Drug resistance in which E2a and PRC2 drive changes in the B-cell epigenome; these alterations attenuate alkylating agent treatment-induced apoptosis.
Daniel L. Ruderman - One of the best experts on this subject based on the ideXlab platform.
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Epigenetic changes mediated by polycomb repressive complex 2 and E2a are associated with Drug resistance in a mouse model of lymphoma
Genome medicine, 2016Co-Authors: Colin Flinders, Larry Lam, Liudmilla Rubbi, Roberto Ferrari, Sorel Fitz-gibbon, Pao-yang Chen, Michael C. Thompson, Heather R. Christofk, David B. Agus, Daniel L. RudermanAbstract:Background The genetic origins of chemotherapy resistance are well established; however, the role of epigenetics in Drug resistance is less well understood. To investigate mechanisms of Drug resistance, we performed systematic genetic, epigenetic, and transcriptomic analyses of an alkylating agent-sensitive murine lymphoma cell line and a series of resistant lines derived by Drug Dose Escalation.
Liudmilla Rubbi - One of the best experts on this subject based on the ideXlab platform.
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Epigenetic changes mediated by polycomb repressive complex 2 and E2a are associated with Drug resistance in a mouse model of lymphoma
Genome medicine, 2016Co-Authors: Colin Flinders, Larry Lam, Liudmilla Rubbi, Roberto Ferrari, Sorel Fitz-gibbon, Pao-yang Chen, Michael C. Thompson, Heather R. Christofk, David B. Agus, Daniel L. RudermanAbstract:Background The genetic origins of chemotherapy resistance are well established; however, the role of epigenetics in Drug resistance is less well understood. To investigate mechanisms of Drug resistance, we performed systematic genetic, epigenetic, and transcriptomic analyses of an alkylating agent-sensitive murine lymphoma cell line and a series of resistant lines derived by Drug Dose Escalation.
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Epigenetic changes mediated by polycomb repressive complex 2 and E2a are associated with Drug resistance in a mouse model of lymphoma
Genome Medicine, 2016Co-Authors: Colin Flinders, Larry Lam, Liudmilla Rubbi, Roberto Ferrari, Sorel Fitz-gibbon, Pao-yang Chen, Heather R. Christofk, Michael Thompson, David Agus, Daniel RudermanAbstract:Background The genetic origins of chemotherapy resistance are well established; however, the role of epigenetics in Drug resistance is less well understood. To investigate mechanisms of Drug resistance, we performed systematic genetic, epigenetic, and transcriptomic analyses of an alkylating agent-sensitive murine lymphoma cell line and a series of resistant lines derived by Drug Dose Escalation. Methods Dose Escalation of the alkylating agent mafosfamide was used to create a series of increasingly Drug-resistant mouse Burkitt’s lymphoma cell lines. Whole genome sequencing, DNA microarrays, reduced representation bisulfite sequencing, and chromatin immunoprecipitation sequencing were used to identify alterations in DNA sequence, mRNA expression, CpG methylation, and H3K27me3 occupancy, respectively, that were associated with increased resistance. Results Our data suggest that acquired resistance cannot be explained by genetic alterations. Based on integration of transcriptional profiles with transcription factor binding data, we hypothesize that resistance is driven by epigenetic plasticity. We observed that the resistant cells had H3K27me3 and DNA methylation profiles distinct from those of the parental lines. Moreover, we observed DNA methylation changes in the promoters of genes regulated by E2a and members of the polycomb repressor complex 2 (PRC2) and differentially expressed genes were enriched for targets of E2a. The integrative analysis considering H3K27me3 further supported a role for PRC2 in mediating resistance. By integrating our results with data from the Immunological Genome Project (Immgen.org), we showed that these transcriptional changes track the B-cell maturation axis. Conclusions Our data suggest a novel mechanism of Drug resistance in which E2a and PRC2 drive changes in the B-cell epigenome; these alterations attenuate alkylating agent treatment-induced apoptosis.
Roberto Ferrari - One of the best experts on this subject based on the ideXlab platform.
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Epigenetic changes mediated by polycomb repressive complex 2 and E2a are associated with Drug resistance in a mouse model of lymphoma
Genome medicine, 2016Co-Authors: Colin Flinders, Larry Lam, Liudmilla Rubbi, Roberto Ferrari, Sorel Fitz-gibbon, Pao-yang Chen, Michael C. Thompson, Heather R. Christofk, David B. Agus, Daniel L. RudermanAbstract:Background The genetic origins of chemotherapy resistance are well established; however, the role of epigenetics in Drug resistance is less well understood. To investigate mechanisms of Drug resistance, we performed systematic genetic, epigenetic, and transcriptomic analyses of an alkylating agent-sensitive murine lymphoma cell line and a series of resistant lines derived by Drug Dose Escalation.
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Epigenetic changes mediated by polycomb repressive complex 2 and E2a are associated with Drug resistance in a mouse model of lymphoma
Genome Medicine, 2016Co-Authors: Colin Flinders, Larry Lam, Liudmilla Rubbi, Roberto Ferrari, Sorel Fitz-gibbon, Pao-yang Chen, Heather R. Christofk, Michael Thompson, David Agus, Daniel RudermanAbstract:Background The genetic origins of chemotherapy resistance are well established; however, the role of epigenetics in Drug resistance is less well understood. To investigate mechanisms of Drug resistance, we performed systematic genetic, epigenetic, and transcriptomic analyses of an alkylating agent-sensitive murine lymphoma cell line and a series of resistant lines derived by Drug Dose Escalation. Methods Dose Escalation of the alkylating agent mafosfamide was used to create a series of increasingly Drug-resistant mouse Burkitt’s lymphoma cell lines. Whole genome sequencing, DNA microarrays, reduced representation bisulfite sequencing, and chromatin immunoprecipitation sequencing were used to identify alterations in DNA sequence, mRNA expression, CpG methylation, and H3K27me3 occupancy, respectively, that were associated with increased resistance. Results Our data suggest that acquired resistance cannot be explained by genetic alterations. Based on integration of transcriptional profiles with transcription factor binding data, we hypothesize that resistance is driven by epigenetic plasticity. We observed that the resistant cells had H3K27me3 and DNA methylation profiles distinct from those of the parental lines. Moreover, we observed DNA methylation changes in the promoters of genes regulated by E2a and members of the polycomb repressor complex 2 (PRC2) and differentially expressed genes were enriched for targets of E2a. The integrative analysis considering H3K27me3 further supported a role for PRC2 in mediating resistance. By integrating our results with data from the Immunological Genome Project (Immgen.org), we showed that these transcriptional changes track the B-cell maturation axis. Conclusions Our data suggest a novel mechanism of Drug resistance in which E2a and PRC2 drive changes in the B-cell epigenome; these alterations attenuate alkylating agent treatment-induced apoptosis.
