Aberrant DNA methylation of p57KIP2 identifies a cell-cycle regulatory pathway with prognostic impact in adult acute lymphocytic leukemia

Shen, Ling; Toyota, Minoru; Kondo, Yutaka; Obata, Toshiro; Daniel, Sophia; Pierce, Sherry; Imai, Kohzoh; Kantarjian, Hagop M.; Issa, Jean–Pierre J.; Garcia‐Manero, Guillermo

doi:10.1182/blood-2002-08-2466

Cited by 117 publications

(98 citation statements)

References 19 publications

(31 reference statements)

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“…In contrast to this study and a recent one investigating childhood ALL [1], Shen et al [5] reported 50% methylation in p57 in adult ALL. Moreover, concurrent methylation of p15, p57, and p73 was infrequent (3% of non-Ph1 ALLs) when compared to adult patients (22%) [5].…”

Section: Resultscontrasting

confidence: 99%

“…Moreover, concurrent methylation of p15, p57, and p73 was infrequent (3% of non-Ph1 ALLs) when compared to adult patients (22%) [5]. This is a significant obser- vation since a higher proportion of pediatric cases are not associated with the Ph1 chromosome (>95%) than in adult patients (about 75%).…”

Section: Resultsmentioning

confidence: 92%

“…The methylation status of the CIP/ KIP family is not completely known. p57 is methylated in 50% of adult ALL but apparently is rare in childhood ALL [1,5]. Methylation of p21 appears now to be rare in most cancers [6].…”

mentioning

confidence: 99%

“…p73 is methylated in about 20% of childhood and adult ALL [1][2][3][4] while data is scarce for p27, p53, and Rb. One-fourth of non-Ph1 ALLs with poor outcome in adults carries methylation in one gene from each family, i.e., p73, p57, and p15 [5]. No information is available for childhood ALL.…”

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confidence: 99%

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Childhood and adult ALL: Differences in epigenetic lesions associated with cell cycle genes

et al. 2005

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The impact of silencing tumor suppressor genes involved in cell proliferation in adult and pediatric ALL is still unknown. We analyzed methylation of the master regulators (p73, p53, Rb), CDKIs (p27, p57), and the INK4 locus (p15) in childhood ALLs and describe a relatively low frequency. Comparisons with adult ALL showed that p57 clearly differed in children (7% methylation) and adults (50% methylation). While >20% of adult ALL Ph1 chromosome-negative undergo methylation of p73, p57, and p15, only 3% of childhood ALL carried such anomalies, which is very significant when a higher fraction of pediatric patients has non-Ph1 ALL than do the adult patients. We have studied a large p57 CpG island and expression by real-time RT-PCR. We observed that 53% of childhood leukemias lacked p57 transcripts, and the overall level was 8-fold lower than in normal lymphocytes (P < 0.0001). However, no correlation with methylation was found. Thus, loss of p57 expression in the absence of methylation may be frequent in childhood ALL, suggesting that methylation is not the sole mechanism of p57 downregulation. Methylation differences in ALL may be age-related or, alternatively, reflect different pathogenesis. Am.

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Section: Resultscontrasting

confidence: 99%

Section: Resultsmentioning

confidence: 92%

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confidence: 99%

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confidence: 99%

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Childhood and adult ALL: Differences in epigenetic lesions associated with cell cycle genes

et al. 2005

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“…All these cells were cultured in appropriate medium. In addition, we analysed 34 primary ALL, 35 primary acute myeloid leukaemia (AML) and 14 primary multiple myeloma specimens, as described previously (Toyota et al, 2001;Shen et al, 2003).…”

Section: Cell Lines and Specimensmentioning

confidence: 99%

Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours

et al. 2005

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Hypoxia is a key factor contributing to the progression of human neoplasias and to the development of resistance to chemotherapy. BNIP3 is a proapoptotic member of the Bcl-2 protein family involved in hypoxia-induced cell death. We evaluated the expression and methylation status of BNIP3 gene to better understand the role of epigenetic alteration of its expression in haematopoietic tumours. Methylation of the region around the BNIP3 transcription start site was detected in four acute lymphocytic leukaemia, one multiple myeloma and one Burkitt lymphoma cell lines, and was closely associated with silencing the gene. That expression of BNIP3 was restored by treatment with 5-aza2 0 -deoxycytidine (5-aza-dC), a methyltransferase inhibitor, which confirmed the gene to be epigenetically inactivated by methylation. Notably, re-expression of BNIP3 using 5-aza2-dC also restored hypoxia-mediated cell death in methylated cell lines. Acetylation of histone H3 in the 5 0 region of the gene, which was assessed using chromatin immunoprecipitation assays, correlated directly with gene expression and inversely with DNA methylation. Among primary tumours, methylation of BNIP3 was detected in five of 34 (15%) acute lymphocytic leukaemias, six of 35 (17%) acute myelogenous leukaemias and three of 14 (21%) multiple myelomas. These results suggest that aberrant DNA methylation of the 5 0 CpG island and histone deacetylation play key roles in silencing BNIP3 expression in haematopoietic tumours.

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Characterizing the Spectrum of Epigenetic Dysregulation Across Lymphoid Malignancies

Harrop

Dickinson

Johnstone

et al. 2023

Precision Cancer Therapies, Volume 1 ‐ Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies

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Aberrant DNA methylation of p57KIP2 identifies a cell-cycle regulatory pathway with prognostic impact in adult acute lymphocytic leukemia

Cited by 117 publications

References 19 publications

Childhood and adult ALL: Differences in epigenetic lesions associated with cell cycle genes

Childhood and adult ALL: Differences in epigenetic lesions associated with cell cycle genes

Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours

Characterizing the Spectrum of Epigenetic Dysregulation Across Lymphoid Malignancies

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