title: Mechanisms of resistance to decitabine in the myelodysplastic syndrome.
abstract: OBJECTIVE
  The DNA methylation inhibitor 5-aza-2'-deoxycytidine (DAC) is approved for the treatment of myelodysplastic syndromes (MDS), but resistance to DAC develops during treatment and mechanisms of resistance remain unknown. Therefore, we investigated mechanisms of primary and secondary resistance to DAC in MDS.
  
  
  METHODS
  We performed Quantitative Real-Time PCR to examine expression of genes related to DAC metabolism prior to therapy in 32 responders and non-responders with MDS as well as 14 patients who achieved a complete remission and subsequently relapsed while on therapy (secondary resistance). We then performed quantitative methylation analyses by bisulfite pyrosequencing of 10 genes as well as Methylated CpG Island Amplification Microarray (MCAM) analysis of global methylation in secondary resistance.
  
  
  RESULTS
  Most genes showed no differences by response, but the CDA/DCK ratio was 3 fold higher in non-responders than responders (P<.05), suggesting that this could be a mechanism of primary resistance. There were no significant differences at relapse in DAC metabolism genes, and no DCK mutations were detected. Global methylation measured by the LINE1 assay was lower at relapse than at diagnosis (P<.05). On average, the methylation of 10 genes was lower at relapse (16.1%) compared to diagnosis (18.1%) (P<.05). MCAM analysis showed decreased methylation of an average of 4.5% (range 0.6%-9.7%) of the genes at relapse. By contrast, new cytogenetic changes were found in 20% of patients.
  
  
  CONCLUSIONS
  Pharmacological mechanisms are involved in primary resistance to DAC, whereas hypomethylation does not prevent a relapse for patients with DAC treatment.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Taichun
authors.initials: T
authors.lastname: Qin
authors.forename: Ryan
authors.initials: R
authors.lastname: Castoro
authors.forename: Samih
authors.initials: S
authors.lastname: El Ahdab
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelinek
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Wang
authors.forename: Jiali
authors.initials: J
authors.lastname: Si
authors.forename: Jingmin
authors.initials: J
authors.lastname: Shu
authors.forename: Rong
authors.initials: R
authors.lastname: He
authors.forename: Nianxiang
authors.initials: N
authors.lastname: Zhang
authors.forename: Woonbok
authors.initials: W
authors.lastname: Chung
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D002869:Chromosome Aberrations / Q000187:drug effects; D018899:CpG Islands / Q000235:genetics; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D003842:Deoxycytidine Kinase / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D000077209:Decitabine; D003842:Deoxycytidine Kinase; D003564:Cytidine Deaminase; D001374:Azacitidine