Hypermethylation of CpG islands in the promoter region of the p15INK4B gene in childhood acute leukaemia

Tsellou, Erasmia; Troungos, Constantinos; Moschovi, Maria; Athanasiadou-Piperopoulou, Fani; Polychronopoulou, Sophia; Kosmidis, Helen; Kalmanti, Maria; Hatzakis, Angelos; Dessypris, Nick; Kalofoutis, Anastasios; Petridou, Eleni

doi:10.1016/j.ejca.2004.12.010

Cited by 29 publications

(17 citation statements)

References 28 publications

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“…The incidence of CDKN2A/ CDKN2B inactivation by deletions or methylation in childhood pre-B-ALL and T-ALL is high, and therefore suggests an important role for these genes in leukemogenesis. However, the prognostic significance of these deletions is still debated (Hann et al, 2001;Graf et al, 2002;Tsellou et al, 2005;van Zutven et al, 2005;Mirebeau et al, 2006). In a study of 227 cases of childhood B-lineage ALL, inactivation of CDKN2A or CDKN2B, as measured by gene dosage and methylation-specific PCR, did not influence the patients' outcome, although CDKN2A inactivation was more often associated with poor prognostic features in B-lineage ALL (Beverloo, 2006).…”

Section: Discussionmentioning

confidence: 95%

Copy number alterations in childhood acute lymphoblastic leukemia and their association with minimal residual disease

Steinemann

Cario

Stanulla

et al. 2008

Genes Chromosomes & Cancer

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In vivo response to initial therapy, as assessed by determination of minimal residual disease (MRD) after 5 and 12 weeks of treatment, has evolved as a strong prognostic factor in children with acute lymphoblastic leukemia (ALL) treated according to the BFM regime. Individual treatment response may be influenced by copy number alterations (CNA) leading to altered gene expression. We aimed to evaluate CNA using high-resolution array-comparative genomic hybridization (array-CGH) in different treatment-response groups. Leukemic genomic profiles of 25 standard risk (MRD-SR) and 25 high risk (MRD-HR) patients were compared. CNAs were found in 46/50 patients (92%). The most significant difference was a gain of 1q23-qter because of an unbalanced t(1;19), found in 10/25 MRD-SR patients, but in none of the MRD-HR patients (P < 0.001). The most frequent CNAs in the MRD-HR group were deletions of genomic regions harboring the immunoglobulin genes (Ig), e.g., 2p11.2 in 60% of MRD-HR compared to 28% of MRD-SR (P = 0.045). Combining all Ig loci, significantly more MRD-HR than MRD-SR patients displayed deletions (17:8 patients, P = 0.02). Frequency of other CNAs, such as loss of 9p21 or gains of 21q, did not differ strongly between the two patient groups. This is the first study evaluating the clinical significance of CNA as detected by array-CGH in childhood ALL and the first to suggest that such analyses may provide clinically important data. This article contains supplementary material available via the Internet at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

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Section: Discussionmentioning

confidence: 95%

Copy number alterations in childhood acute lymphoblastic leukemia and their association with minimal residual disease

Steinemann

Cario

Stanulla

et al. 2008

Genes Chromosomes & Cancer

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“…a Student's t test. Tsellou et al, 2005) and has been implicated in the control of normal myeloid development (Sakashita et al, 2001). In accord with our results, methylation of CpG35a has been reported to be seen infrequently in normal PBLs, but has been seen commonly in preleukemic and leukemic samples and in normal colon, albeit at a lower level than in the matched colonic tumor samples (Nguyen et al, 2001).…”

Section: Discussionmentioning

confidence: 98%

Detailed methylation analysis of CpG islands on human chromosome region 9p21

Weeks

Morison

2005

Genes Chromosomes & Cancer

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Deletion of 9p21 is the most commonly reported chromosomal abnormality in pediatric acute lymphoblastic leukemia, and published data suggest that the maternal chromosome is preferentially deleted. Preferential maternal deletion of 9p21 and reports of a differentially methylated region (DMR) and of parental effects in mice with lymphoma suggest there may be an unrecognized imprinted locus in this region. To screen for DMRs, we used the mcrBC/HpaII screening method and peripheral-blood DNA. Of 36 CpG islands within an 8.5-Mb region of 9p21, seven were identified as putative DMRs and were further analyzed by bisulfite sequencing. Neither any of the CpG islands nor a previously published putative DMR nearby showed evidence of differential parental methylation; however, the published DMR did demonstrate sequence-dependent differential methylation. Our data, which showed heterogeneous and low-level methylation of CpG islands, have obvious implications for methylation studies.

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“…51-68 chromosomes detected in karyotype) and DNA methylation and subsequent reduced expression of the tumour suppressor genes FHIT and p53 implicates the involvement of epigenetics in the pathogenesis of CL (Davidsson et al, 2009;Zheng et al, 2004b). In some cases of MLL-rearranged infant leukaemia (mainly the ones with t(4;11) and t(11;19) translocations) and childhood ALL, extensive hypermethylation of tumour suppressor genes such as FHIT, DLX3, p16 and p15 resulting in gene silencing has been observed (Maloney et al, 1998;Nakamura et al, 1999;Stam et al, 2006;Stumpel et al, 2009;Tsellou et al, 2005). For instance, hypermethylation of p15 INK4B has been reported to be more frequently observed in B-and T-cell ALL than in AML (Iravani et al, 1997;Tsellou et al, 2005).…”

Section: Methods Of Detecting Leukaemic Cell Proliferationmentioning

confidence: 99%

“…In some cases of MLL-rearranged infant leukaemia (mainly the ones with t(4;11) and t(11;19) translocations) and childhood ALL, extensive hypermethylation of tumour suppressor genes such as FHIT, DLX3, p16 and p15 resulting in gene silencing has been observed (Maloney et al, 1998;Nakamura et al, 1999;Stam et al, 2006;Stumpel et al, 2009;Tsellou et al, 2005). For instance, hypermethylation of p15 INK4B has been reported to be more frequently observed in B-and T-cell ALL than in AML (Iravani et al, 1997;Tsellou et al, 2005). On the other hand, studies has demonstrated epigenetic inactivation of tumour suppressor genes Early B-cell Factor 3 (EBF3) and metallothionein III (MT3) via aberrant methylation in a majority of…”

Section: Methods Of Detecting Leukaemic Cell Proliferationmentioning

confidence: 99%

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

Choi¹,

Polcher²,

Joas³

2016

EFSA Supporting Publications

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This report presents the outcomes of a systematic review (SR) identifying the mechanisms and chemicals involved in the pathogenesis of Parkinson's disease (PD) and childhood leukaemia (CL). This work serves as a basis for defining and mapping the causal linkages between a molecular initiating event (MIE) and a final adverse outcome (AO) that are relevant for the development of a prototype adverse outcome pathway (AOP) for assessing risk factors for PD and CL. Search for literature from 1990 to present was conducted using Web of Science, PubMed and TOXNET, and relevant references were selected using established inclusion/exclusion criteria and ranked using a set of quality control factors.For PD, 7,384 individual references were identified to be relevant for PD pathogenesis and chemicals associated with PD. Dopaminergic neurodegeneration in the substantia nigra leading to locomotor deficits was identified as the AO in PD. Other identified key events in PD pathogenesis include mitochondrial dysfunction, cellular accumulation of alpha-synuclein and oxidative stress. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, rotenone and paraquat are some chemicals identified to be associated with PD pathogenesis.For CL, 1,988 individual references were identified to be relevant for CL pathogenesis and chemicals associated with CL. Chromosomal translocation, genetic damage/mutation and hyperdiploidy are considered as driving forces of CL. Except for infant leukaemia, CL pathogenesis requires a 'two-hit' model with an initiating event occurring in utero followed by a secondary hit potentially occurring after birth. Potential MIEs leading to these driving mechanisms include aberrant DNA topoisomerase II activity and erroneous DNA repair. Epigenetics appears to also play an influential role in CL pathogenesis. Benzene, bioflavonoids and organophosphates are some chemicals identified to be implicated in CL pathogenesis.The challenges of developing AOPs for these two diseases and the data gaps identified from the outcomes of this SR are also elaborated in this report. The present document has been produced and adopted by the bodies identified above as authors. This task has been carried out exclusively by the authors in the context of a contract between the European Food Safety Authority and the authors, awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors. KEY WORDSSystematic Review, Parkinson Disease, Childhood Leukaemia, Pathogenesis, Chemicals, Pesticides, Adverse Outcome Pathway SUMMARYThe aim of this project was to perform a systematic review (SR) to collect relevant publications related to the mechanisms involved in the pathogenesis of Parkinson's disease (PD)...

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Hypermethylation of CpG islands in the promoter region of the p15INK4B gene in childhood acute leukaemia

Cited by 29 publications

References 28 publications

Copy number alterations in childhood acute lymphoblastic leukemia and their association with minimal residual disease

Copy number alterations in childhood acute lymphoblastic leukemia and their association with minimal residual disease

Detailed methylation analysis of CpG islands on human chromosome region 9p21

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

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