Abstract
BackgroundThe 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.MethodsDose 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.ResultsOur 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0305-0) contains supplementary material, which is available to authorized users.
Highlights
The genetic origins of chemotherapy resistance are well established; the role of epigenetics in drug resistance is less well understood
half maximal effective concentration (EC50), 857 ± 68 nM; R4000 EC50 3446 ± 138 nM, mean ± standard error of the mean), we initially hypothesized that acquired resistance was mediated by genetic variants that were enriched in the population over the course of the dose escalation
We found that members of the polycomb repressive complex 2 (PRC2) Suz12 and Pcl2 were very strongly enriched over positively covarying genes, suggesting an involvement of this complex in mediating epigenetic changes during the acquisition of drug resistance
Summary
The genetic origins of chemotherapy resistance are well established; 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. Burkitt’s lymphoma is extremely aggressive [4], 90–95 % of children receiving the standard-of-care therapy, a combination treatment of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, enter complete remission. Treatment of adults is not as successful [5], in part due to acquired resistance In both children and adults, salvage treatment has a poor success rate, with only one-third of children and very few adults obtaining positive outcomes from salvage therapy
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