Expression levels of DNA methyltransferase genes do not correlate with p15INK4B gene methylation in myelodysplastic syndromes

Aoki, Etsuko; Ohashi, Haruhiko; Uchida, Toshiki; Murate, Takashi; Saito, Hidehiko; Kinoshita, Tomohiro

doi:10.1038/sj.leu.2403046

Cited by 21 publications

(7 citation statements)

References 8 publications

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“…The frequency of p15 hypermethylation in paediatric MDS other than JMML was 78%, which was comparable with that in adult MDS. In contrast, we found that the frequency of p15 hypermethylation was much lower in patients with JMML (3/18; 17%) than adults with each subtype of MDS or with CMML (Uchida et al , 1997; Quesnel et al , 1998; Daskalakis et al , 2002; Aoki et al , 2003; Tessema et al , 2003). The clinical and laboratory characteristics of the three patients with p15 hypermethylation were not different from those of the others.…”

Section: Discussioncontrasting

confidence: 58%

“…The aberrant methylation of tumour‐suppressor genes is now recognized as a well‐established event in the development and progression of solid tumours and haematological malignancies (Jones & Laird, 1999; Herman & Baylin, 2003). Several studies have reported that the p15 gene, encoding a CDK inhibitor, is frequently methylated in adult patients with acute leukaemia and MDS (Herman et al , 1997; Uchida et al , 1997; Quesnel et al , 1998; Cameron et al , 1999; Guo et al , 2000; Wong et al , 2000; Toyota et al , 2001; Daskalakis et al , 2002; Garcia‐Manero et al , 2002, 2003; Aoki et al , 2003; Gutierrez et al , 2003; Tessema et al , 2003). In paediatric patients with acute lymphoblastic leukaemia (ALL) and AML, p15 was methylated as frequently as in adult patients (Herman et al , 1997; Guo et al , 2000; Wong et al , 2000; Garcia‐Manero et al , 2003; Gutierrez et al , 2003).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2005

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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.

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Section: Discussioncontrasting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

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

et al. 2005

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“…Notably, in some cases of cancer, overexpression of DNMT1 does not necessarily result in hypermethylation of its downstream genes (47,48). Moreover, a number of reports also demonstrate that hypermethylation of some DNMT1 target genes does not require increased DNMT1 expression (49,50).…”

Section: Discussionmentioning

confidence: 99%

hNaa10p contributes to tumorigenesis by facilitating DNMT1-mediated tumor suppressor gene silencing

Lee¹,

Ou²,

Lee³

et al. 2010

J. Clin. Invest.

103

111

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Hypermethylation-mediated tumor suppressor gene silencing plays a crucial role in tumorigenesis. Understanding its underlying mechanism is essential for cancer treatment. Previous studies on human N-α-acetyltransferase 10, NatA catalytic subunit (hNaa10p; also known as human arrest-defective 1 [hARD1]), have generated conflicting results with regard to its role in tumorigenesis. Here we provide multiple lines of evidence indicating that it is oncogenic. We have shown that hNaa10p overexpression correlated with poor survival of human lung cancer patients. In vitro, enforced expression of hNaa10p was sufficient to cause cellular transformation, and siRNA-mediated depletion of hNaa10p impaired cancer cell proliferation in colony assays and xenograft studies. The oncogenic potential of hNaa10p depended on its interaction with DNA methyltransferase 1 (DNMT1). Mechanistically, hNaa10p positively regulated DNMT1 enzymatic activity by facilitating its binding to DNA in vitro and its recruitment to promoters of tumor suppressor genes, such as E-cadherin, in vivo. Consistent with this, interaction between hNaa10p and DNMT1 was required for E-cadherin silencing through promoter CpG methylation, and E-cadherin repression contributed to the oncogenic effects of hNaa10p. Together, our data not only establish hNaa10p as an oncoprotein, but also reveal that it contributes to oncogenesis through modulation of DNMT1 function.

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“…In preleukemic samples, stratification for different levels of blast expansion (ie comparison of RAEB-1 vs RAEB-2 vs RAEB-t) might reveal a correlation of p15 methylation with DNMT overexpression only in patients with a higher percentage of blasts. Finally, overexpression in leukemic cell lines compared to MDS in the present study 1 points towards a further dysregulation of the methylation machinery during the in vitro expansion of cultured cells compared to primary samples. Taken together, it appears more likely that locally restricted, gene-specific regulatory mechanisms may be operative in promoting gene-specific hypermethylation in myeloid malignancies.…”

mentioning

confidence: 89%

Gene silencing of the p15/INK4B cell-cycle inhibitor by hypermethylation: an early or later epigenetic alteration in myelodysplastic syndromes?

Lübbert

2003

Leukemia

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In their paper published in this issue of Leukemia, Aoki and et al 1 have addressed important questions regarding the mechanisms mediating a regional, inactiving promoter methylation of the p15/INK4B gene in myelodysplastic syndromes (MDS). Based on a recent report of coordinate overexpression of DNA methyltransferase (DNMT) -1, -3a and -3b, and a correlation between p15 methylation and DNMT overexpression in acute myeloid leukemia (AML; Mizuno et al 2 ), they asked whether this correlation is also present in MDS. They demonstrate overexpression of DNMT1 and DNMT3b in several control leukemia cell lines, even after equalizing mRNA levels to a cell-cycle-dependent gene (histone H4, necessary to compensate for the known DNMT expression changes during cell cycle). However, no significant increase in DNMT expression was apparent in mononuclear cells from MDS patients compared to those from individuals with normal bone marrow. Furthermore, mRNA expression levels of the three DNMTs did not significantly differ between MDS cases with vs without p15 promoter methylation.In the majority of solid tumors and hematologic neoplasias, hypermethylation of numerous genes, which are otherwise both unmethylated and expressed in a regulated manner in the normal cellular counterparts, can be detected. 3,4 These include p16 and p15, p14/ARF, p21/WAF, p73, BRCA1, MTMG6, GSTP-1, RASSF1A, VHL, E-cadherin, estrogen receptor, androgen receptor, and calcitonin. Thus, genes encoding proteins involved in control of cell proliferation and differentiation, detoxification, DNA repair, signalling, adhesion, and metastasis can be inactivated by this epigenetic mechanism in cancer. Some of the targets of cancer-associated methylation are putative or bona fide tumor suppressor genes. Thus, epigenetic inactivation is considered an oncogenic event similar to genetic alterations of tumor suppressors, such as mutations or deletions. Hypermethylation patterns in malignancy may be quite tissue-specific: for instance, p16 is frequently methylated in epithelial neoplasias, non-Hodgkin's lymphoma, and multiple myeloma, but only rarely in myeloid neoplasias, in which, however, the closely related p15 is frequently silenced. 5 Both p15 and p16 are inhibitors of cyclin-dependent kinases (CDK) 4 and 6, thus controlling G1/S transition in the cell cycle, with p15 being a downstream target of TGF-b under physiologic conditions. While their functions are of some redundance as to CDK inhibition, p15 inactivation by methylation or deletion appears to be specific both in a mouse model of radiation-induced hematopoietic malignancy 6 and in primary myeloid neoplasia. The phenotype of knockout mice with homozygous deletion of the p15 gene is associated with lymphoproliferative neoplasias, tumors, and cysts. 7Expression of p15 in normal hematopoiesis. It is both lineage-restricted and regulated: p15 is not expressed in G0/G1-arrested CD34+ cells from bone marrow or peripheral blood, but upregulated in CD34+ cells mobilized by chemotherapy (with or without additional G-C...

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Expression levels of DNA methyltransferase genes do not correlate with p15INK4B gene methylation in myelodysplastic syndromes

Cited by 21 publications

References 8 publications

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

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

hNaa10p contributes to tumorigenesis by facilitating DNMT1-mediated tumor suppressor gene silencing

Gene silencing of the p15/INK4B cell-cycle inhibitor by hypermethylation: an early or later epigenetic alteration in myelodysplastic syndromes?

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