p16/MTS1/INK4A gene is frequently inactivated by hypermethylation in childhood acute lymphoblastic leukemia with 11q23 translocation

Nakamura, Makoto; Sugita, Kanji; Inukai, Takeshi; Goi, Kumiko; Iijima, K; Tezuka, Tohru; Kojika, Satoru; Shiraishi, Kyoko; Miyamoto, Naohiko; Karakida, Naoko; Kagami, Keiko; O-Koyama, T; Mori, Toshiki; Nakazawa, Shinpei

doi:10.1038/sj.leu.2401437

Cited by 48 publications

(34 citation statements)

References 6 publications

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“…26 Moreover, hypermethylation of p16 have been associated with disease progression inT-ALL, 27 while epigenetic modification of the ER has been associated with better outcome in AML. 28 Few reports that have studied childhood ALL mostly include single candidate genes [29][30][31] and only limited data are available on the extent of concurrent hypermethylation. 32 It is likely that the biology of childhood ALL is different from adult ALL and that different leukemogenic events control these disease entities.…”

Section: Introductionmentioning

confidence: 99%

Concurrent methylation of multiple genes in childhood ALL: Correlation with phenotype and molecular subgroup

et al. 2003

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Multiple genes have been shown to be independently hypermethylated in lymphoid malignancies. We report here on the extent of concurrent methylation of E-cadherin, Dap-kinase, O 6 MGMT, p73, p16, p15 and p14 in 129 pediatric ALL cases. While most of these genes demonstrated methylation in a proportion of cases, O 6 MGMT, p16 and p14 were infrequently methylated (11, 7 and 3%, respectively). Methylation of at least one gene was found in the vast majority (83%) of cases. To determine the extent and concordance of methylation we calculated a methylation index (MI ¼ number of methylated genes/number of studied genes) for each sample. The average MI was 0.28, corresponding to 2/7 methylated genes. MI was correlated with standard prognostic factors, including immunophenotype, age, sex, WBC and presence of specific translocations (TEL-AML1, BCR-ABL, E2A-PBX1 or MLL-AF4). We determined that children X10 years old and children presenting with high WBC (X50 Â 10 9 /l) both associated with a higher MI (Po0.01 and o0.05, respectively). T-ALLs demonstrated a lower MI (median ¼ 0.17) than precursor B ALLs (median ¼ 0.28). Among the different molecular subgroups, MLL-ALLs had the highest MI (mean ¼ 0.35), while ALLs carrying the t(1;19) had the lowest MI (mean ¼ 0.07). The most common epigenetic lesion in childhood ALL was methylation of E-cadherin (72%) independent of the molecular subtype or other clinicopathological factors.

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Section: Introductionmentioning

confidence: 99%

Concurrent methylation of multiple genes in childhood ALL: Correlation with phenotype and molecular subgroup

et al. 2003

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“…However, methylation as a means to inactivate genes has been demonstrated in ALL for the calcitonin, p15 and p16 genes. [38][39][40][41] More recently, methylation of p73, a target of the ABL kinase, has been reported in approximately 30% of ALLs and Burkitt's lymphomas, 42 suggesting that methylation could be a mechanism of gene silencing of tumor suppressor genes in these diseases. The ATM gene deficient in ataxia-telangiectasia, a recessive multisystem disease associated with a high risk of lymphomas and leukemias, was found previously to be inactivated in a A proposed model of leukemia pathogenesis following emergence of the Ph chromosome.…”

Section: Discussionmentioning

confidence: 99%

ABL1 methylation in Ph-positive ALL is exclusively associated with the P210 form of BCR-ABL

et al. 2001

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In human Ph-positive leukemia there is a clear association of different forms of the BCR-ABL oncogene with distinct types of leukemia. The P190 form of BCR-ABL is rarely observed in chronic myeloid leukemia (CML) but is present in 50% of Phpositive acute lymphoblastic leukemia (ALL). In contrast, the P210 form is observed both in CML and 50% of Ph-positive ALL. Methylation of the proximal promoter of the ABL1 gene has been shown to be a nearly universal event associated with clinical progression of CML. This raises the question of whether methylation of the ABL1 promoter is an epigenetic modification also associated with Ph-positive ALL. To study this issue, we used methylation-specific PCR and bisulfite sequencing to determine the methylation status of the ABL1 promoter in 18 Ph-positive ALL samples. We report here that gene-specific ABL1 promoter methylation is associated mainly with the P210 form of BCR-ABL and not the P190 form. While six out of the seven P210-positive ALL samples had ABL1 promoter methylation, none of the 11 P190-positive ALL samples demonstrated ABL1 promoter methylation. In addition, we estimated the extent and relative abundance of ABL1 promoter methylation in several Ph-positive ALL samples and compared it to the methylation pattern in chronic, accelerated and blastic crisis phases of CML. We put forth a model that correlates the different types of leukemias with the different levels of ABL1 promoter methylation. Leukemia (2001) 15, 575-582.

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“…The procedure is described in our previous report. 6 To confirm the amount and integrity of genomic DNA for each sample, blots were rehybridized with a probe prepared from human CD13 cDNA. The ratio of the signal by the p16 probe to that by the CD13 probe was used to define the presence of homozygous or hemizygous p16 deletion.…”

Section: Figurementioning

confidence: 99%

“…Some BCL10 gene abnormalities were proposed to be found only in RNA and not in genomic DNA, 4,5 but no previous studies investigated DNA and RNA at the same time. [4][5][6][7][8] To make the matter clear, we first analyzed the mutations of BCL10 RNA from 43 lymphomas, and for those lymphomas with RNA alterations we investigated the genomic DNA extracted from the same tumor and normal tissues from the same patients.…”

Section: To the Editormentioning

confidence: 99%

Abnormalities of the p16INK4a gene in childhood B-precursor acute lymphoblastic leukemia without nonrandom translocations: analysis of seven matched pairs of primary leukemia and corresponding cell line

et al. 2001

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p16/MTS1/INK4A gene is frequently inactivated by hypermethylation in childhood acute lymphoblastic leukemia with 11q23 translocation

Cited by 48 publications

References 6 publications

Concurrent methylation of multiple genes in childhood ALL: Correlation with phenotype and molecular subgroup

Concurrent methylation of multiple genes in childhood ALL: Correlation with phenotype and molecular subgroup

ABL1 methylation in Ph-positive ALL is exclusively associated with the P210 form of BCR-ABL

Abnormalities of the p16INK4a gene in childhood B-precursor acute lymphoblastic leukemia without nonrandom translocations: analysis of seven matched pairs of primary leukemia and corresponding cell line

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