title: Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma.
abstract: Although aberrant DNA methylation patterning is a hallmark of cancer, the relevance of targeting DNA methyltransferases (DNMT) remains unclear for most tumors. In diffuse large B-cell lymphoma (DLBCL) we observed that chemoresistance is associated with aberrant DNA methylation programming. Prolonged exposure to low-dose DNMT inhibitors (DNMTI) reprogrammed chemoresistant cells to become doxorubicin sensitive without major toxicity in vivo. Nine genes were recurrently hypermethylated in chemoresistant DLBCL. Of these, SMAD1 was a critical contributor, and reactivation was required for chemosensitization. A phase I clinical study was conducted evaluating azacitidine priming followed by standard chemoimmunotherapy in high-risk patients newly diagnosed with DLBCL. The combination was well tolerated and yielded a high rate of complete remission. Pre- and post-azacitidine treatment biopsies confirmed SMAD1 demethylation and chemosensitization, delineating a personalized strategy for the clinical use of DNMTIs.
  
  
  CONCLUSIONS
  The problem of chemoresistant DLBCL remains the most urgent challenge in the clinical management of patients with this disease. We describe a mechanism-based approach toward the rational translation of DNMTIs for the treatment of high-risk DLBCL.
authors: 1Division of Hematology and Oncology, Department of Medicine, 2Division of Biostatistics and Epidemiology, Department of Public Health, 3Weill Cornell Cancer Center, and Departments of 4Pathology and 5Pharmacology, Weill Cornell Medical College, Cornell University, New York, New York; 6Section of Hematology/Oncology, Department of Medicine, The University of Chicago; Department of Pathology, Northwestern University, Chicago, Illinois; 8Institute for Research in Immunology and Cancer and Department of Pathology and Cell Biology, University of Montreal, Montreal, Quebec; 9Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada; 10IBM Research, Rio de Janeiro, Brazil; and 11Department of Oncological Sciences, University of Turin, Turin, Italy.
authors: Thomas
authors: T
authors: Clozel
authors: ShaoNing
authors: S
authors: Yang
authors: Rebecca L
authors: RL
authors: Elstrom
authors: Wayne
authors: W
authors: Tam
authors: Peter
authors: P
authors: Martin
authors: Matthias
authors: M
authors: Kormaksson
authors: Samprit
authors: S
authors: Banerjee
authors: Aparna
authors: A
authors: Vasanthakumar
authors: Biljana
authors: B
authors: Culjkovic
authors: David W
authors: DW
authors: Scott
authors: Sarah
authors: S
authors: Wyman
authors: Micheal
authors: M
authors: Leser
authors: Rita
authors: R
authors: Shaknovich
authors: Amy
authors: A
authors: Chadburn
authors: Fabrizio
authors: F
authors: Tabbo
authors: Lucy A
authors: LA
authors: Godley
authors: Randy D
authors: RD
authors: Gascoyne
authors: Katherine L
authors: KL
authors: Borden
authors: Giorgio
authors: G
authors: Inghirami
authors: John P
authors: JP
authors: Leonard
authors: Ari
authors: A
authors: Melnick
authors: Leandro
authors: L
authors: Cerchietti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D001374:Azacitidine / Q000009:adverse effects / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D019175:DNA Methylation / Q000235:genetics*; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics*; D008875:Middle Aged; D034622:RNA Interference; D034741:RNA, Small Interfering; D051898:Smad1 Protein / Q000235:genetics; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D034741:RNA, Small Interfering; C497399:SMAD1 protein, human; D051898:Smad1 Protein; D004317:Doxorubicin; D015254:DNA Modification Methylases; D001374:Azacitidine
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