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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.
Flinders, Colin; Lam, Larry; Rubbi, Liudmilla; Ferrari, Roberto; Fitz-Gibbon, Sorel; Chen, Pao-Yang; Thompson, Michael; Christofk, Heather; B Agus, David; Ruderman, Daniel; Mallick, Parag; Pellegrini, Matteo.
Afiliación
  • Flinders C; Department of Biological Chemistry, University of California, Los Angeles, CA, 90095, USA.
  • Lam L; Center for Applied Molecular Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • Rubbi L; Department of Molecular, Cellular and Developmental Biology, University of California, Los Angeles, CA, 90095, USA.
  • Ferrari R; Department of Molecular, Cellular and Developmental Biology, University of California, Los Angeles, CA, 90095, USA.
  • Fitz-Gibbon S; Department of Molecular, Cellular and Developmental Biology, University of California, Los Angeles, CA, 90095, USA.
  • Chen PY; Department of Molecular, Cellular and Developmental Biology, University of California, Los Angeles, CA, 90095, USA.
  • Thompson M; Department of Molecular, Cellular and Developmental Biology, University of California, Los Angeles, CA, 90095, USA.
  • Christofk H; Department of Molecular, Cellular and Developmental Biology, University of California, Los Angeles, CA, 90095, USA.
  • B Agus D; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, 90095, USA.
  • Ruderman D; Department of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • Mallick P; Center for Applied Molecular Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • Pellegrini M; Department of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
Genome Med ; 8(1): 54, 2016 05 04.
Article en En | MEDLINE | ID: mdl-27146673
ABSTRACT

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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfoma de Burkitt / Resistencia a Antineoplásicos / Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico / Complejo Represivo Polycomb 2 / Antineoplásicos Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Genome Med Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfoma de Burkitt / Resistencia a Antineoplásicos / Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico / Complejo Represivo Polycomb 2 / Antineoplásicos Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Genome Med Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos