Alterations of the p53, p21, p16, p15 and RAS genes in childhood T-cell acute lymphoblastic leukemia

Kawamura, Minoru; Ohnìshì, H.; Guo, Shu-Xia; Sheng, Xiaojing; Minegishi, Masayoshi; Hanada, Ryoji; Horibe, Keizo; Hongo, Teruaki; Kaneko, Yasuhiko; Bessho, Fumio; Yamaguchi, Masayoshi; Sekiya, Takao; Hayashi, Yasuhide

doi:10.1016/s0145-2126(98)00146-5

Cited by 123 publications

(91 citation statements)

References 52 publications

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“…28 Similarly, mutations of the p53 gene occurred in only three of 57 patients (5%) with T-ALL at diagnosis and one of 14 patients (7%) at relapse, whereas p53 mutations were found in 67% of 18 T cell ALL cell lines. 31 Bax frameshift mutations as a possible cause for the observed reduction of Bax protein expression in the relapsed ALL cells were absent at initial diagnosis and relapse as could be expected from a recent study. 32 However, using the same protocol we were able to detect bax frameshift mutations in Lovo cells which were therefore used routinely as a positive control (data not shown).…”

Section: Discussionsupporting

confidence: 74%

Relapse in childhood acute lymphoblastic leukemia is associated with a decrease of the Bax/Bcl-2 ratio and loss of spontaneous caspase-3 processing in vivo

et al. 2000

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Dysfunction of the p53/Bax/caspase-3 apoptosis signaling pathway has been shown to play a role in tumorigenesis and tumor progression, ie the development of acquired drug resistance. Low expression of the apoptosis inducer Bax correlates with poor response to therapy and shorter overall survival in solid tumors. In the present study, we analyzed the p53/Bax/caspase-3 pathway in a paired and an unpaired sample series of children with acute lymphoblastic leukemia (ALL) at initial diagnosis and relapse. The data demonstrate that both Bax expression levels and the Bax/Bcl-2 ratio are significantly lower in samples at relapse as compared with samples at initial diagnosis (P = 0.013, Wilcoxon signed rank test (paired samples); P = 0.0039, Mann-Whitney U test (unpaired samples)). The loss of Bax protein expression was not a consequence of Bax frameshift mutations of the G 8 tract and could not be attributed to mutations of the p53 coding sequence (exons 5 to 8) which were detected to a similar extent in de novo ALL samples and at relapse. Analysis of the downstream effector caspase-3 showed loss of spontaneous caspase-3 processing at relapse. Whereas nine out of 14 (64%, paired samples) or 37 out of 77 (48%, unpaired samples) ALL patients at initial diagnosis displayed spontaneous in vivo processing of caspase-3, this was completely absent in patients at relapse (paired samples) or detected in only one out of 34 patients at relapse (2.9%, unpaired samples). We therefore conclude that in ALL relapse a severe disturbance of apoptotic pathways occurs, both at the level of Bax expression and caspase-3 activation. Leukemia (2000) 14, 1606-1613.

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Section: Discussionsupporting

confidence: 74%

Relapse in childhood acute lymphoblastic leukemia is associated with a decrease of the Bax/Bcl-2 ratio and loss of spontaneous caspase-3 processing in vivo

et al. 2000

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“…56 Similarly, although the incidence of p53 mutations is high in T-ALL cell lines, mutations are infrequent in clinical samples at diagnosis. 57 Given the low incidence of p53 mutations it would seem unlikely that the pattern of p53 expression observed in blasts from three T-ALL patients would be due directly to p53 mutations. However, p53 stabilization and impairment of transcriptional activity has been noted in adult T cell leukemia/lymphoma.…”

Section: Discussionmentioning

confidence: 93%

Diversity of the apoptotic response to chemotherapy in childhood leukemia

et al. 2002

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Apoptosis is the primary mechanism through which most chemotherapeutic agents induce tumor cell death. The purpose of this study was to determine the extent to which blasts from children with leukemia undergo a uniform apoptotic death pathway in vivo. The expression of pro-and anti-apoptotic proteins p53, p21, MDM-2, BCL-2, BCL-X L , BCL-X S , and BAX, and caspase-3 activity was determined in circulating blasts collected from the peripheral blood of children with leukemia prior to, and at serial time points following chemotherapy. Culturing blasts ex vivo for 12 h assessed spontaneous apoptosis and the increment induced by chemotherapy. Baseline apoptosis varied between 3% and 29%. Twenty-four hours following chemotherapy the increase in the percentage of cells undergoing apoptosis ranged from Ͻ1% to 38%. Eleven of 20 patients who received initial treatment with a p53-dependent drug showed an increase in p53 expression. In these patients, the levels of p53 target genes were also increased. A uniform pattern of BCL-2 family protein expression was not observed and only a minority of samples showed a change that would favor apoptosis. We conclude that that the initial apoptotic response to chemotherapy in children with leukemia is variable involving both p53-dependent and p53-independent pathways.

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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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Alterations of the p53, p21, p16, p15 and RAS genes in childhood T-cell acute lymphoblastic leukemia

Cited by 123 publications

References 52 publications

Relapse in childhood acute lymphoblastic leukemia is associated with a decrease of the Bax/Bcl-2 ratio and loss of spontaneous caspase-3 processing in vivo

Relapse in childhood acute lymphoblastic leukemia is associated with a decrease of the Bax/Bcl-2 ratio and loss of spontaneous caspase-3 processing in vivo

Diversity of the apoptotic response to chemotherapy in childhood leukemia

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

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