Negative Effect of DNA Hypermethylation on the Outcome of Intensive Chemotherapy in Older Patients with High-Risk Myelodysplastic Syndromes and Acute Myeloid Leukemia following Myelodysplastic Syndrome

Abstract

We show for the first time a significant effect of methylation status on the outcome of conventional chemotherapy in high-risk MDS and acute myelogenous leukemia following MDS. Provided confirmed in an independent study, our results should be used as a basis for therapeutic decision-making in this patient group.

Maintenance treatment with azacytidine for patients with high‐risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy

“…All patients gave their written informed consent. Diagnosis as well as CR was verified at a central haematopathology unit according to established Nordic MDS Group routines (Jädersten et al, 2005;Grövdal et al, 2007). Bone marrow cellularity was assessed on bone marrow biopsies and the percentage of blasts in bone marrow smears was determined by counting 500 cells in representative areas.…”

“…Samples were shipped to arrive at a central laboratory within 24 h (Lund) for isolation of mononuclear cells (MNC) and CD34 + cells by density gradient technique (Lymphoprep; Axis Shield, Oslo, Norway) and magnetic bead cell sorting (MACS; Miltenyi Biotech, Bergisch-Gladbach, Germany) as previously described (Nilsson et al, 2002;Grövdal et al, 2007). Cells were stored as pellet at )80°C.…”

“…Genomic DNA was isolated from MNC and CD34 + cells using the QiAmp DNA mini kit (Qiagen, Hilden, Germany) according to manufacturer's guidelines. Bone marrow sampled in CR and during follow up frequently rendered an insufficient CD34 + yield, and methylation analyses were therefore consequently performed on un-separated MNC, after first confirming a strong correlation between methylation results in CD34 + and MNC on the pre-induction samples (P < 0AE001) (Grövdal et al, 2007). The amount of DNA obtained was measured by spectrophotometer (ND-100; Nano-Drop Technologies, Wilmington, DE, USA).…”

“…Promoter-methylation of these genes has also been reported to be associated with poor prognosis and leukaemic transformation of MDS (Tien et al, 2001;Christiansen et al, 2003;Aggerholm et al, 2006). We recently reported a strong association between promoter-methylation of CDH1 or of more than one of these three genes and failure to induction chemotherapy (Grövdal et al, 2007). The present study was designed to assess the feasibility and efficacy of long-term maintenance treatment with azacytidine in a cohort of elderly patients with high-risk MDS and AML following MDS in CR after conventional induction chemotherapy.…”

Gene-specific and global methylation patterns predict outcome in patients with acute myeloid leukemia

“…[7][8][9] In high-risk myelodysplastic syndrome (MDS) and in AML after MDS, methylation of CDKN2b (p15), E-cadherin (CDH) and hypermethylated in cancer 1 (HIC1) have recently been shown to be associated with failure to achieve complete remission (CR) after induction chemotherapy. 10 We analyzed gene-specific promoter methylation of p15, CDH and HIC1 as well as global DNA methylation using the luminometric methylation assay (LUMA) technique in a well-characterized cohort of 107 AML patients. Furthermore, we examined genome-wide CpG island-associated promoter methylation of 27 578 promoter CpG sites, corresponding to 14 495 individual genes, in 20 AML patients using the Illumina HumanMethylation27 BeadChip.…”