Methylation status of the p15 and p16 genes in paediatric myelodysplastic syndrome and juvenile myelomonocytic leukaemia

Abstract

Summary Aberrant DNA methylation is frequently observed in adults with myelodysplastic syndrome (MDS), and is recognized as a critical event in the disease's pathogenesis and progression. This is the first report to investigate the methylation status of p15 and p16, cell cycle regulatory genes, in children with MDS (n = 9) and juvenile myelomonocytic leukaemia (JMML; n = 18) by using a methylation‐specific polymerase chain reaction. The frequency of p15 hypermethylation in paediatric MDS was 78% (7/9), which was comparable to that in adult MDS. In contrast, p15 hypermethylation in JMML was a rare event (17%; 3/18). In JMML, clinical and laboratory characteristics including PTPN11 mutations and aberrant colony formation were not different between the three patients with hypermethylated p15 and the others. Aberrant methylation of p16 was not detected in children with either MDS or JMML. Since p15 and p16 genes were unmethylated in two children with JMML, in whom the disease had progressed with an increased number of blasts, a condition referred to as blastic crisis, we infer that the aberrant methylation of these genes is not responsible for the progression of JMML. The results suggest that demethylating agents may be effective in most children with MDS and a few patients with JMML.

RASA4undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia

“…4 However, the picture of epigenetic modification in JMML is still incomplete because the analysis of aberrant CpG island methylation in JMML has so far been based on candidategene approaches and the results cover just a tiny minority of the ten thousands of promoter CpG islands in the human genome. Even though some of the targets of hypermethylation in JMML are prominent cancer genes such as CDKN2B, 23 their functional contribution to more aggressive clinical behavior remains so far obscure. While RASA4 dysregulation is of interest because of its potential interference with the principal proliferative mechanism in JMML, it cannot be ruled out that aberrant RASA4 methylation in JMML might simply be a collateral effect of a broader hypermethylation phenotype.…”

Response to treatment with azacitidine in children with advanced myelodysplastic syndrome prior to hematopoietic stem cell transplantation

“…Hypermethylation leads to the silencing of regulatory genes and aberrant cell behavior. Furthermore, hypermethylation of the promoters of various genes, such as p15, 15,16 DLX4, 17 p73, 18 and VTRNA1- 3,19 has been associated with unfavorable prognosis in MDS.…”

“…14,15 Implicated genes act as cell differentiation, cell cycle and cell growth regulators, or play roles in the stress response and apoptosis pathways. Hypermethylation leads to the silencing of regulatory genes and aberrant cell behavior.…”

p15INK4b, a Tumor Suppressor in Acute Myeloid Leukemia

“…However, more recently, it was found that even in patients with the RARS subtype, which falls within the lower risk of MDS, p15INK4b was found to be the most frequently methylated gene (>20% of cases) of 25 known tumor suppressors that were evaluated in the study (Valencia et al, 2011). Although most studies have been conducted in MDS in adults, comparable levels of aberrant methylation patterns have been observed in pediatric MDS patients as well (Hasegawa et al, 2005), and a similar correlation with the disease subtypes has been established (Rodrigues et al, 2010). In chronic myelomonocytic leukemia (CMML), aberrant methylation of p15INK4b is found in about 60% of cases and is associated with a high proportion of blastic transformation (Tessema et al, 2003).…”

“…High variability between and within individual patients, consistent with observations in AML patients, were also reported (Tessema et al, 2003, Aggerholm et al, 1999, Cameron et al, 1999. In the pediatric form of the disease, juvenile myelomonocytic leukemia (JMML), p15INK4b hypermethylation is found to be a less frequent, however, still significant event (17% of cases) (Hasegawa et al, 2005). With regards to cytogenetic abnormalities, p15INK4b methylation levels have been found to occur at higher frequencies in AML/MDS patients with an unfavorable karyotype (Wong et al, 2000;Galm et al, 2005;Shimamoto et al, 2005;Markus et al, 2007).…”