Aberrant DNA methylation is a dominant mechanism in MDS progression to AML.
Myelodysplastic syndromes (MDSs) are clonal hematologic disorders that frequently represent an intermediate disease stage before progression to acute myeloid leukemia (AML). As such, study of MDS/AML can provide insight into the mechanisms of neoplastic evolution. In 184 patients with MDS and AML, DNA methylation microarray and high-density single nucleotide polymorphism array (SNP-A) karyotyping were used to assess the relative contributions of aberrant DNA methylation and chromosomal deletions to tumor-suppressor gene (TSG) silencing during disease progression. Aberrant methylation was seen in every sample, on average affecting 91 of 1505 CpG loci in early MDS and 179 of 1505 loci after blast transformation (refractory anemia with excess blasts [RAEB]/AML). In contrast, chromosome aberrations were seen in 79% of early MDS samples and 90% of RAEB/AML samples, and were not as widely distributed over the genome. Analysis of the most frequently aberrantly methylated genes identified FZD9 as a candidate TSG on chromosome 7. In patients with chromosome deletion at the FZD9 locus, aberrant methylation of the remaining allele was associated with the poorest clinical outcome. These results indicate that aberrant methylation can cooperate with chromosome deletions to silence TSG. However, the ubiquity, extent, and correlation with disease progression suggest that aberrant DNA methylation is the dominant mechanism for TSG silencing and clonal variation in MDS evolution to AML.
Jiang
Ying
Y
Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clinic, OH 44195, USA.
Dunbar
Andrew
A
Gondek
Lukasz P
LP
Mohan
Sanjay
S
Rataul
Manjot
M
O'Keefe
Christine
C
Sekeres
Mikkael
M
Saunthararajah
Yogen
Y
Maciejewski
Jaroslaw P
JP
D000293:Adolescent; D000328:Adult; D000368:Aged; D000753:Anemia, Refractory / Q000235:genetics / Q000473:pathology; D000754:Anemia, Refractory, with Excess of Blasts / Q000235:genetics / Q000473:pathology; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002869:Chromosome Aberrations; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D051157:Frizzled Receptors / Q000235:genetics*; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
C105574:FZD3 protein, human; D051157:Frizzled Receptors; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D025521:Tumor Suppressor Proteins