Mutational and methylation analysis of the cyclin‐dependent kinase 4 inhibitor (p16INK4A) gene in chronic lymphocytic leukemia

Tsirigotis, Panagiotis; Pappa, Vassiliki; Labropoulos, Stefanos; Papageorgiou, Sotirios; Kontsioti, Frinda; Dervenoulas, John; Papageorgiou, Efstathios; Panani, Anna D.; Mantzios, Georgios; Economopoulos, Theofanis; Raptis, Sotirios A.

doi:10.1111/j.1600-0609.2005.00604.x

Cited by 15 publications

(12 citation statements)

References 42 publications

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“…A methylation frequency of 12% was shown in CLL patients in this study. Few studies reported methylation in 6-18% of CLL patients (Nosaka et al, 2000;Chim et al, 2006a;Tsirigotis et al, 2006;Seeliger et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

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DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

Bodoor

Haddad

Alkhateeb

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Aberrant DNA methylation of tumor suppressor genes has been reported in all major types of leukemia with potential involvement in the inactivation of regulatory cell cycle and apoptosis genes. However, most of the previous reports did not show the extent of concurrent methylation of multiple genes in the four leukemia types. Here, we analyzed six key genes (p14, p15, p16, p53, DAPK and TMS1) for DNA methylation using methylation specific PCR to analyze peripheral blood of 78 leukemia patients (24 CML, 25 CLL, 12 AML, and 17 ALL) and 24 healthy volunteers. In CML, methylation was detected for p15 (11%), p16 (9%), p53 (23%) and DAPK (23%), in CLL, p14 (25%), p15 (19%), p16 (12%), p53 (17%) and DAPK (36%), in AML, p14 (8%), p15 (45%), p53 (9%) and DAPK (17%) and in ALL, p15 (14%), p16 (8%), and p53 (8%). This study highlighted an essential role of DAPK methylation in chronic leukemia in contrast to p15 methylation in the acute cases, whereas TMS1 hypermethylation was absent in all cases. Furthermore, hypermethylation of multiple genes per patient was observed, with obvious selectiveness in the 9p21 chromosomal region genes (p14, p15 and p16). Interestingly, methylation of p15 increased the risk of methylation in p53, and vice versa, by five folds (p=0.03) indicating possible synergistic epigenetic disruption of different phases of the cell cycle or between the cell cycle and apoptosis. The investigation of multiple relationships between methylated genes might shed light on tumor specific inactivation of the cell cycle and apoptotic pathways.

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Section: Discussionmentioning

confidence: 99%

“…In CLL patients, methylation was reported in p15 (Nguyen et al, 2001;Chim et al, 2006;Seeliger et al, 2009), p16 (Nosaka et al, 2000;Chim et al, 2006a;Tsirigotis et al, 2006;Seeliger et al, 2009) and DAPK (Katzenellenbogen et al, 1999;Chim et al, 2006b).…”

Section: Introductionmentioning

confidence: 99%

DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

Bodoor

Haddad

Alkhateeb

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…Most previous studies in CLL, examined the methylation status of p16, another member of the INK4 family, demonstrating a low frequency [2,6,7]. More recently Chim et al, have shown by MS-PCR, p15 promoter methylation in 36% and p16 in 14% of newly diagnosed Chinese patients with CLL and these abnormalities did not correlate with age, stage, sex, and overall survival [8].…”

Section: Discussionmentioning

confidence: 99%

Hypermethylation of the p15^INK4B gene promoter in B‐chronic lymphocytic leukemia

et al. 2007

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The p15 gene is a putative tumor suppressor gene that encodes a member of the cyclin dependent kinase inhibitors. Inactivation of p15 by promoter hypermethylation has been postulated as a possible way by which tumor suppressor genes are inactivated in cancer. In this study, we examined the methylation status of the p15 gene promoter in 34 patients with B‐Chronic Lymphocytic Leukemia (B‐CLL), by the Methylation‐Specific Polymerase Chain Reaction. Selective methylation of the p15 gene promoter was found in 4/34 cases (11.8%). According to Rai staging, the four patients with methylated p15 were staged on diagnosis as: 1 on Stage 0, 1 in Stage I, 1 in Stage III, and 1 in Stage IV. Our results suggest that methylation of the p15 gene promoter can be detected in a small subset of B‐CLL patients, at all stages of the disease. Am. J. Hematol., 2007. © 2007 Wiley‐Liss, Inc.

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“…INK4A [96] and p15 INK4B [97] genes have also been described in small proportion of CLL patients, however the clinical significance from these small studies are yet undefined.…”

Section: Methylation Of P16mentioning

confidence: 99%

Aberrant Methylation in Hematological Malignancies

Thirukonda¹,

Raghupathy²,

Parekh³

2012

Translational

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Epigenetics encompasses heritable changes in gene expression without alterations in genetic sequence. Among the multiple epigenetic regulators of gene expression, methylation of cytosine in genomic DNA is amongst the most stable and best studied. Expanding knowledge of aberrant methylation in hematological malignancies has increased its applicability in diagnosis, classification, prognostication and prediction of treatment response. Genome-wide methylation profiling can differentiate between clinically relevant subtypes of non-hodgkin's lymphoma (NHL) as well as distinguish monoclonal gammopathy of unknown significance (MGUS) from multiple myeloma (MM). New subcategories of normal karyotype acute myeloid leukemia (AML) with distinct canonical pathways and different disease behavior have also been identified by methylation studies. Methylation scores can predict outcomes in chronic lymphocytic leukemia (CLL). Genes with tumor suppressor function are frequently silenced by methylation and may be amenable to therapeutic intervention. DNA hypomethylating agents azacitidine and decitabine have been approved by the FDA for treatment of myelodysplastic syndrome (MDS). Clinical trials of newer agents including histone deacetylase inhibitors (HDAC-i) are showing great promise in different hematological malignancies. High-resolution methylation analysis using massively parallel sequencing (MPS) is likely to further improve our understanding of disease pathogenesis and identify novel therapeutic approaches in hematological malignancies. In this review article we will describe recent advances in methylation studies and the current and potential future impact of this knowledge on management of hematological malignancies.

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Mutational and methylation analysis of the cyclin‐dependent kinase 4 inhibitor (p16^INK4A) gene in chronic lymphocytic leukemia

Abstract: These results indicate that genetic alterations of p16 gene are rare events in patients with CLL. The clarification of the role of p16 gene promoter methylation in the pathogenesis and evolution of CLL needs further investigation.

Cited by 15 publications

References 42 publications

DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

Hypermethylation of the p15^INK4B gene promoter in B‐chronic lymphocytic leukemia

Aberrant Methylation in Hematological Malignancies

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Mutational and methylation analysis of the cyclin‐dependent kinase 4 inhibitor (p16INK4A) gene in chronic lymphocytic leukemia

Abstract: These results indicate that genetic alterations of p16 gene are rare events in patients with CLL. The clarification of the role of p16 gene promoter methylation in the pathogenesis and evolution of CLL needs further investigation.

Cited by 15 publications

References 42 publications

DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

Hypermethylation of the p15INK4B gene promoter in B‐chronic lymphocytic leukemia

Aberrant Methylation in Hematological Malignancies

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Product

Resources

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Mutational and methylation analysis of the cyclin‐dependent kinase 4 inhibitor (p16^INK4A) gene in chronic lymphocytic leukemia

Hypermethylation of the p15^INK4B gene promoter in B‐chronic lymphocytic leukemia