Impact of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and MGMT expression on dacarbazine resistance of Hodgkin's lymphoma cells

Stefanie Kewitz; Martina Stiefel; Christof M Kramm; Martin S Staege

doi:10.1016/j.leukres.2013.11.001

Impact of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and MGMT expression on dacarbazine resistance of Hodgkin's lymphoma cells

Leuk Res. 2014 Jan;38(1):138-43. doi: 10.1016/j.leukres.2013.11.001. Epub 2013 Nov 13.

Authors

Stefanie Kewitz¹, Martina Stiefel¹, Christof M Kramm², Martin S Staege³

Affiliations

¹ Department of Pediatrics, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
² Department of Pediatrics, Martin-Luther-University Halle-Wittenberg, Halle, Germany; Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, Göttingen, Germany.
³ Department of Pediatrics, Martin-Luther-University Halle-Wittenberg, Halle, Germany. Electronic address: martin.staege@medizin.uni-halle.de.

PMID: 24284332
DOI: 10.1016/j.leukres.2013.11.001

Abstract

We analyzed the methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter and mRNA expression in HL cells and assessed the response of these cells to dacarbazine. Expression of MGMT correlated with the presence of non-methylated promoters and cell lines with non-methylated promoters showed increased resistance against dacarbazine. KM-H2 cells expressed fusion transcripts between MGMT and proline-rich coiled-coil 2B (PRRC2B) but no wild type MGMT transcripts. Dacarbazine sensitivity suggested that fusion transcripts are translated into a protein with reduced functionality. MGMT promoter methylation predicts dacarbazine sensitivity of HL cells and it might be interesting to analyze this factor in HL patients.

Keywords: Dacarbazine; Hodgkin's lymphoma; O6-methylguanine-DNA methyltransferase; Promoter methylation.

MeSH terms

Antineoplastic Agents, Alkylating / pharmacology
Azacitidine / pharmacology
Cell Line, Tumor
Cell Survival / drug effects
Cell Survival / genetics
DNA Methylation*
Dacarbazine / antagonists & inhibitors
Dacarbazine / pharmacology*
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics
Drug Synergism
Gene Expression Regulation, Enzymologic / drug effects
Gene Expression Regulation, Neoplastic / drug effects
Hodgkin Disease / genetics
Hodgkin Disease / metabolism
Hodgkin Disease / pathology
Humans
Immunoblotting
O(6)-Methylguanine-DNA Methyltransferase / genetics*
O(6)-Methylguanine-DNA Methyltransferase / metabolism
Promoter Regions, Genetic / genetics*
Purines / pharmacology
Reverse Transcriptase Polymerase Chain Reaction

Substances

Antineoplastic Agents, Alkylating
Purines
Dacarbazine
O(6)-Methylguanine-DNA Methyltransferase
Azacitidine
lomeguatrib