{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:41:50Z","timestamp":1787064110129,"version":"build-2736575974"},"reference-count":56,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,12,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Chemoresistance remains a challenging clinical problem in the treatment of many lymphoma patients. Epigenetic derangements have been implicated in both intrinsic and acquired chemoresistance. Mutations in epigenetic processes shift entire networks of signaling pathways. They influence tumor suppressors, the DNA-damage response, cell-cycle regulators, and apoptosis. Epigenetic alterations have also been implicated in contributing to immune evasion. Although increased DNA methylation at CpG sites is the most widely studied alteration, increased histone methylation and decreased histone acetylation have also been implicated in stem-like characteristics and highly aggressive disease states as demonstrated in both preclinical models of lymphoma and patient studies. These changes are nonrandom, occur in clusters, and are observed across many lymphoma subtypes. Although caution must be taken when combining epigenetic therapies with other antineoplastic agents, epigenetic therapies have rarely induced clinical meaningful responses as single agents. Epigenetic priming of chemotherapy, targeted therapies, and immunotherapies in lymphoma patients may create opportunities to overcome resistance.<\/jats:p>","DOI":"10.1182\/hematology.2020000092","type":"journal-article","created":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T21:56:59Z","timestamp":1607119019000},"page":"85-94","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":8,"title":["Can we use epigenetics to prime chemoresistant lymphomas?"],"prefix":"10.1182","volume":"2020","author":[{"given":"Jennifer E.","family":"Amengual","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"10168","key":"2020121621165725900_B1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/S0140-6736(18)32984-2","article-title":"Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial","volume":"393","author":"Horwitz","year":"2019","journal-title":"Lancet"},{"issue":"4","key":"2020121621165725900_B2","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1182\/blood-2017-09-806737","article-title":"A phase 1 study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T-cell lymphoma","volume":"131","author":"Amengual","year":"2018","journal-title":"Blood"},{"issue":"6","key":"2020121621165725900_B3","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1093\/genetics\/28.6.491","article-title":"Mutations of bacteria from virus sensitivity to virus resistance","volume":"28","author":"Luria","year":"1943","journal-title":"Genetics"},{"issue":"5","key":"2020121621165725900_B4","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.semcancer.2010.10.005","article-title":"Lethal mutagenesis: targeting the mutator phenotype in cancer","volume":"20","author":"Fox","year":"2010","journal-title":"Semin Cancer Biol"},{"issue":"4","key":"2020121621165725900_B5","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s10585-018-9903-0","article-title":"The challenge of drug resistance in cancer treatment: a current overview","volume":"35","author":"Nikolaou","year":"2018","journal-title":"Clin Exp Metastasis"},{"issue":"17","key":"2020121621165725900_B6","doi-asserted-by":"crossref","first-page":"4663","DOI":"10.1158\/0008-5472.CAN-14-0118","article-title":"Resistance to chemotherapy: patient variability and cellular heterogeneity","volume":"74","author":"Kessler","year":"2014","journal-title":"Cancer Res"},{"issue":"47","key":"2020121621165725900_B7","doi-asserted-by":"crossref","first-page":"7512","DOI":"10.1038\/sj.onc.1206951","article-title":"Strategies for reversing drug resistance","volume":"22","author":"Fojo","year":"2003","journal-title":"Oncogene"},{"key":"2020121621165725900_B8","article-title":"Harnessing lymphoma epigenetics to improve therapies","volume":"2020","author":"Yang","year":"2020","journal-title":"Hematology Am Soc Hematol Educ Program"},{"issue":"1","key":"2020121621165725900_B9","doi-asserted-by":"crossref","first-page":"e1003137","DOI":"10.1371\/journal.pgen.1003137","article-title":"Aberration in DNA methylation in B-cell lymphomas has a complex origin and increases with disease severity","volume":"9","author":"De","year":"2013","journal-title":"PLoS Genet"},{"issue":"9","key":"2020121621165725900_B10","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1186\/s13059-014-0472-5","article-title":"Dynamic evolution of clonal epialleles revealed by methclone","volume":"15","author":"Li","year":"2014","journal-title":"Genome Biol"},{"key":"2020121621165725900_B11","doi-asserted-by":"crossref","first-page":"6921","DOI":"10.1038\/ncomms7921","article-title":"Epigenomic evolution in diffuse large B-cell lymphomas","volume":"6","author":"Pan","year":"2015","journal-title":"Nat Commun"},{"issue":"1","key":"2020121621165725900_B12","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s13073-016-0305-0","article-title":"Epigenetic changes mediated by polycomb repressive complex 2 and E2a are associated with drug resistance in a mouse model of lymphoma","volume":"8","author":"Flinders","year":"2016","journal-title":"Genome Med"},{"issue":"22","key":"2020121621165725900_B13","doi-asserted-by":"crossref","DOI":"10.1182\/blood.V128.22.3932.3932","article-title":"A pharmacologically reversible epigenomic signature of relapse and chemotherapy resistance in anaplastic large cell lymphoma [abstract]","volume":"128","author":"Pan","year":"2016","journal-title":"Blood"},{"issue":"9","key":"2020121621165725900_B14","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1158\/2159-8290.CD-13-0117","article-title":"Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma","volume":"3","author":"Clozel","year":"2013","journal-title":"Cancer Discov"},{"issue":"1","key":"2020121621165725900_B15","doi-asserted-by":"crossref","first-page":"21","DOI":"10.18632\/oncoscience.288","article-title":"EZH2 inhibition re-sensitizes multidrug resistant B-cell lymphomas to etoposide mediated apoptosis","volume":"3","author":"Smonskey","year":"2016","journal-title":"Oncoscience"},{"issue":"8","key":"2020121621165725900_B16","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1158\/1078-0432.CCR-17-0443","article-title":"Overcoming resistance to DNA-targeted agents by epigenetic activation of Schlafen 11 (SLFN11) expression with class I histone deacetylase inhibitors","volume":"24","author":"Tang","year":"2018","journal-title":"Clin Cancer Res"},{"issue":"2","key":"2020121621165725900_B17","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.ccell.2017.01.006","article-title":"Chemosensitive relapse in small cell lung cancer proceeds through an EZH2-SLFN11 axis","volume":"31","author":"Gardner","year":"2017","journal-title":"Cancer Cell"},{"issue":"10","key":"2020121621165725900_B18","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/s41580-019-0143-1","article-title":"The roles of DNA, RNA and histone methylation in ageing and cancer","volume":"20","author":"Michalak","year":"2019","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"7015","key":"2020121621165725900_B19","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1038\/nature03114","article-title":"Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks","volume":"432","author":"Huyen","year":"2004","journal-title":"Nature"},{"issue":"2","key":"2020121621165725900_B20","doi-asserted-by":"crossref","first-page":"373","DOI":"10.3324\/haematol.2016.144964","article-title":"Inhibition of demethylase KDM6B sensitizes diffuse large B-cell lymphoma to chemotherapeutic drugs","volume":"102","author":"Mathur","year":"2017","journal-title":"Haematologica"},{"issue":"22","key":"2020121621165725900_B21","doi-asserted-by":"crossref","first-page":"5827","DOI":"10.1182\/blood-2010-10-312603","article-title":"Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma","volume":"117","author":"Piekarz","year":"2011","journal-title":"Blood"},{"issue":"6","key":"2020121621165725900_B22","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1200\/JCO.2011.37.4223","article-title":"Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy","volume":"30","author":"Coiffier","year":"2012","journal-title":"J Clin Oncol"},{"issue":"12","key":"2020121621165725900_B23","doi-asserted-by":"crossref","first-page":"4636","DOI":"10.1182\/blood-2003-09-3068","article-title":"T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy: impact of depsipeptide on molecular markers, therapeutic targets, and mechanisms of resistance","volume":"103","author":"Piekarz","year":"2004","journal-title":"Blood"},{"issue":"2","key":"2020121621165725900_B24","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s00432-015-2026-y","article-title":"Vorinostat, a histone deacetylase (HDAC) inhibitor, promotes cell cycle arrest and re-sensitizes rituximab- and chemo-resistant lymphoma cells to chemotherapy agents","volume":"142","author":"Xue","year":"2016","journal-title":"J Cancer Res Clin Oncol"},{"issue":"4","key":"2020121621165725900_B25","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1111\/bjh.13318","article-title":"Entinostat, a novel histone deacetylase inhibitor is active in B-cell lymphoma and enhances the anti-tumour activity of rituximab and chemotherapy agents","volume":"169","author":"Frys","year":"2015","journal-title":"Br J Haematol"},{"issue":"6","key":"2020121621165725900_B26","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.leukres.2012.02.021","article-title":"Histone deacetylase inhibition restores cisplatin sensitivity of Hodgkin\u2019s lymphoma cells","volume":"36","author":"Kewitz","year":"2012","journal-title":"Leuk Res"},{"issue":"14","key":"2020121621165725900_B27","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.1182\/blood-2016-08-736066","article-title":"HDAC6 inhibition upregulates CD20 levels and increases the efficacy of anti-CD20 monoclonal antibodies","volume":"130","author":"Bobrowicz","year":"2017","journal-title":"Blood"},{"issue":"1","key":"2020121621165725900_B28","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/s41419-019-2210-0","article-title":"Novel HDAC inhibitor chidamide synergizes with rituximab to inhibit diffuse large B-cell lymphoma tumour growth by upregulating CD20","volume":"11","author":"Guan","year":"2020","journal-title":"Cell Death Dis"},{"issue":"11","key":"2020121621165725900_B29","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1038\/s41388-018-0550-3","article-title":"Dual inhibition of PI3K signaling and histone deacetylation halts proliferation and induces lethality in mantle cell lymphoma","volume":"38","author":"Guo","year":"2019","journal-title":"Oncogene"},{"issue":"8","key":"2020121621165725900_B30","doi-asserted-by":"crossref","first-page":"14017","DOI":"10.18632\/oncotarget.14876","article-title":"Dual inhibition of histone deacetylases and phosphoinositide 3-kinase enhances therapeutic activity against B cell lymphoma","volume":"8","author":"Mondello","year":"2017","journal-title":"Oncotarget"},{"issue":"7","key":"2020121621165725900_B31","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1038\/leu.2016.357","article-title":"Histone deacetylase inhibitors interrupt HSP90\u2022RASGRP1 and HSP90\u2022CRAF interactions to upregulate BIM and circumvent drug resistance in lymphoma cells","volume":"31","author":"Ding","year":"2017","journal-title":"Leukemia"},{"issue":"19","key":"2020121621165725900_B32","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1182\/blood-2017-06-792150","article-title":"Synergy of BCL2 and histone deacetylase inhibition against leukemic cells from cutaneous T-cell lymphoma patients","volume":"130","author":"Cyrenne","year":"2017","journal-title":"Blood"},{"issue":"12","key":"2020121621165725900_B33","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1182\/blood-2013-02-485441","article-title":"Sirtuin and pan-class I\/II deacetylase (DAC) inhibition is synergistic in preclinical models and clinical studies of lymphoma","volume":"122","author":"Amengual","year":"2013","journal-title":"Blood"},{"issue":"1","key":"2020121621165725900_B34","doi-asserted-by":"crossref","first-page":"16495","DOI":"10.1038\/s41598-019-52714-4","article-title":"Suppression of BCL6 function by HDAC inhibitor mediated acetylation and chromatin modification enhances BET inhibitor effects in B-cell lymphoma cells","volume":"9","author":"Cortiguera","year":"2019","journal-title":"Sci Rep"},{"issue":"4","key":"2020121621165725900_B35","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1038\/ng1018","article-title":"Acetylation inactivates the transcriptional repressor BCL6","volume":"32","author":"Bereshchenko","year":"2002","journal-title":"Nat Genet"},{"issue":"1","key":"2020121621165725900_B36","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s13046-020-1536-x","article-title":"Enhanced histone H3 acetylation of the PD-L1 promoter via the COP1\/c-Jun\/HDAC3 axis is required for PD-L1 expression in drug-resistant cancer cells","volume":"39","author":"Wang","year":"2020","journal-title":"J Exp Clin Cancer Res"},{"issue":"1","key":"2020121621165725900_B37","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.cell.2017.06.007","article-title":"De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation","volume":"170","author":"Ghoneim","year":"2017","journal-title":"Cell"},{"issue":"6316","key":"2020121621165725900_B38","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1126\/science.aaf2807","article-title":"Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade","volume":"354","author":"Pauken","year":"2016","journal-title":"Science"},{"issue":"3","key":"2020121621165725900_B39","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/nri.2017.108","article-title":"The diverse functions of the PD1 inhibitory pathway","volume":"18","author":"Sharpe","year":"2018","journal-title":"Nat Rev Immunol"},{"issue":"6","key":"2020121621165725900_B40","doi-asserted-by":"crossref","first-page":"2431","DOI":"10.4049\/jimmunol.1502643","article-title":"Genetic and epigenetic regulation of PD-1 expression","volume":"196","author":"Bally","year":"2016","journal-title":"J Immunol"},{"issue":"9","key":"2020121621165725900_B41","doi-asserted-by":"crossref","first-page":"3813","DOI":"10.1172\/JCI99760","article-title":"Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy","volume":"128","author":"Goswami","year":"2018","journal-title":"J Clin Invest"},{"issue":"4","key":"2020121621165725900_B42","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1158\/2159-8290.CD-18-1090","article-title":"Molecular and genetic characterization of MHC deficiency identifies EZH2 as therapeutic target for enhancing immune recognition","volume":"9","author":"Ennishi","year":"2019","journal-title":"Cancer Discov"},{"issue":"3","key":"2020121621165725900_B43","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1158\/2159-8290.CD-19-0116","article-title":"Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma","volume":"10","author":"Mondello","year":"2020","journal-title":"Cancer Discov"},{"issue":"3","key":"2020121621165725900_B44","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/s41408-019-0195-7","article-title":"Genomic analyses of microdissected Hodgkin and Reed-Sternberg cells: mutations in epigenetic regulators and p53 are frequent in refractory classic Hodgkin lymphoma [letter]","volume":"9","author":"Mata","year":"2019","journal-title":"Blood Cancer J"},{"issue":"7","key":"2020121621165725900_B45","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1182\/blood-2012-02-408542","article-title":"Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters","volume":"120","author":"Lemonnier","year":"2012","journal-title":"Blood"},{"issue":"8","key":"2020121621165725900_B46","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1182\/blood-2011-11-391748","article-title":"IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma","volume":"119","author":"Cairns","year":"2012","journal-title":"Blood"},{"issue":"15","key":"2020121621165725900_B47","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1182\/blood-2015-05-644591","article-title":"IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma","volume":"126","author":"Wang","year":"2015","journal-title":"Blood"},{"issue":"10","key":"2020121621165725900_B48","doi-asserted-by":"crossref","first-page":"4316","DOI":"10.1172\/JCI129317","article-title":"Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy","volume":"129","author":"Xu","year":"2019","journal-title":"J Clin Invest"},{"issue":"21","key":"2020121621165725900_B49","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.1182\/blood-2018-04-840538","article-title":"Treatment with 5-azacytidine induces a sustained response in patients with angioimmunoblastic T-cell lymphoma","volume":"132","author":"Lemonnier","year":"2018","journal-title":"Blood"},{"issue":"17","key":"2020121621165725900_B50","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1182\/blood.2019001285","article-title":"Oral 5-azacytidine and romidepsin exhibit marked activity in patients with PTCL: a multicenter phase 1 study","volume":"134","author":"O\u2019Connor","year":"2019","journal-title":"Blood"},{"issue":"2","key":"2020121621165725900_B51","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.3892\/ol.2016.4774","article-title":"TIM-3 expression in lymphoma cells predicts chemoresistance in patients with adult T-cell leukemia\/lymphoma","volume":"12","author":"Horlad","year":"2016","journal-title":"Oncol Lett"},{"issue":"1","key":"2020121621165725900_B52","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1186\/s13148-019-0752-8","article-title":"Molecular and immune correlates of TIM-3 (HAVCR2) and galectin 9 (LGALS9) mRNA expression and DNA methylation in melanoma","volume":"11","author":"Holderried","year":"2019","journal-title":"Clin Epigenetics"},{"key":"2020121621165725900_B53","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s13148-016-0245-y","article-title":"Combinatorial epigenetic therapy in diffuse large B cell lymphoma pre-clinical models and patients","volume":"8","author":"Pera","year":"2016","journal-title":"Clin Epigenetics"},{"issue":"20","key":"2020121621165725900_B54","doi-asserted-by":"crossref","first-page":"5506","DOI":"10.1182\/blood-2011-02-336891","article-title":"HDAC inhibitors and decitabine are highly synergistic and associated with unique gene-expression and epigenetic profiles in models of DLBCL","volume":"118","author":"Kalac","year":"2011","journal-title":"Blood"},{"issue":"suppl 1","key":"2020121621165725900_B55","article-title":"Dual epigenetic agents plus rituximab-gemcitabine-oxaliplatin as a salvage treatment in relapsed\/refractory diffuse large B cell lymphoma patients [abstract]","volume":"134","author":"Qu","year":"2019","journal-title":"Blood"},{"issue":"17","key":"2020121621165725900_B56","doi-asserted-by":"crossref","first-page":"5271","DOI":"10.1158\/1078-0432.CCR-18-3989","article-title":"Precision targeting with EZH2 and HDAC inhibitors in epigenetically dysregulated lymphomas","volume":"25","author":"Lue","year":"2019","journal-title":"Clin Cancer Res"}],"container-title":["Hematology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/hematology\/article-pdf\/2020\/1\/85\/1794922\/hem2020000092c.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/hematology\/article-pdf\/2020\/1\/85\/1794922\/hem2020000092c.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T09:22:05Z","timestamp":1669972925000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/hematology\/article\/2020\/1\/85\/474339\/Can-we-use-epigenetics-to-prime-chemoresistant"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,4]]},"references-count":56,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12,4]]}},"URL":"https:\/\/doi.org\/10.1182\/hematology.2020000092","relation":{},"ISSN":["1520-4391","1520-4383"],"issn-type":[{"value":"1520-4391","type":"print"},{"value":"1520-4383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,4]]}}}