IER3 Expression in Childhood Myelodysplastic Syndrome,

Childhood myelodysplastic syndrome (MDS) is a rare disease accounting for less than 5% of all hematological malignancies. In about 50% of the MDS cases an abnormal karyotype is found by conventional karyotyping, of which chromosome 6 is involved in 10%. The immediate-early-response 3 (IER3) gene, which is located on chromosome 6p21, encodes for a glycoprotein that plays a role in the regulation of apoptosis and cell cycle progression. Recently, it was shown that IER3 gene aberrations frequently occur in adult MDS patients, which are not restricted to patients with chromosome 6 aberrations and that low IER3 expression was associated with a worse outcome. Therefore, we investigated the frequency and prognostic impact of IER3 expression in childhood MDS.

IER3 mRNA expression was determined by quantitative real-time PCR in 58 childhood MDS patients of which 17 carried a chromosome 6 aberration, and in normal bone marrow (n=8). In addition, methylation-specific-PCR (MSP) was performed to investigate the methylation status of the promoter region of the IER3 gene, as a plausible cause for the downregulation of IER3.

Median IER3 mRNA expression was 0.9% in MDS (range 0.01–73.3% relative to GAPDH expression) and 3.3% in normal bone marrow (range 0.81–85.5% relative to GAPDH expression) (p=0.05). A more than 4-fold decrease in IER3 expression below the mean of healthy controls was found in 74% (43/58) of the childhood MDS patients. There was no difference in IER3 mRNA expression between MDS patients with or without chromosome 6 aberrations (MWU p= 0.89). Also, no difference in IER3 mRNA expression was found between the different WHO-subtypes or between primary versus secondary MDS. Three patients with a chromosome 6p21 rearrangements in the IER3 region based on genomic profiling (array-CGH) showed expression-levels in the range of normal bone marrow. Low IER3 mRNA expression was associated with adverse outcome in childhood MDS patients (Cox regression analysis estimated hazard ratio 0.73, p=0.027, 95% CI-interval 0.55–0.97). The low IER3 expression appeared not to be due to hypermethylation of its promoter region.

IER3 expression is low in childhood MDS patients with and without chromosome 6 aberrations and this low expression is associated with poor outcome. However this seems to be due to therapy related mortality, rather than by the increased risk of relapse. The IER3 downregulation is not regulated by hypermethylation of the IER3 promoter region.

Hasle:Pfizer: Research Funding.