Further evidence for the lack of correlation between the breakpoint site within M-BCR and CML prognosis and for the occasional involvement of p53 in transformation

Aguiar, Ricardo C.T.; Dahia, Patricia L.M.; Bendit, Israel; Beitler, Beatriz; Dorlhiac, Pedro; Bydlowski, Sérgio Paulo; Chamone, Dalton de Alencar Fischer

doi:10.1016/0165-4608(95)00096-8

Cited by 13 publications

(5 citation statements)

References 41 publications

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“…DNA was obtained using standard methods (2). RNA was available from 32 primary tumours and most of the cell lines and was extracted with Trizol (Gibco BRL, Gaithersburg, MD) according to the manufacturer's guidelines.…”

Section: Dna and Rna Extractionmentioning

confidence: 99%

“…Chromosomal translocations resulting in novel fusion proteins or transcriptional activation of an oncogene by juxtaposition of a T cell receptor or immunoglobulin gene (1) are usually present at initial diagnosis of leukaemias and lymphomas. Conversely, inactivation of tumour suppressor genes seems to play a more relevant role, albeit not exclusively, in disease progression, usually with ominous prognostic implications (2,3). Moreover, the chromosomal disruptions leading to such abnormalities are not evenly distributed throughout the genome, but rather cluster in certain regions.…”

Section: Introductionmentioning

confidence: 99%

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PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanismsin haematological malignancies

Dahia

Aguiar

Alberta

et al. 1999

Human Molecular Genetics

255

156

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PTEN is a novel tumour suppressor gene that encodes a dual-specificity phosphatase with homology to adhesion molecules tensin and auxillin. It recently has been suggested that PTEN dephosphorylates phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3, 4,5)P3], which mediates growth factor-induced activation of intracellular signalling, in particular through the serine-threonine kinase Akt, a known cell survival-promoting factor. PTEN has been mapped to 10q23.3, a region disrupted in several human tumours including haematological malignancies. We have analysed PTEN in a series of primary acute leukaemias and non-Hodgkin's lymphomas (NHLs) as well as in cell lines. We have also examined whether a correlation could be found between PTEN and Akt levels in these samples. We show here that the majority of cell lines studied carries PTEN abnormalities. At the structural level, we found mutations and hemizygous deletions in 40% of these cell lines, while a smaller number of primary haematological malignancies, in particular NHLs, carries PTEN mutations. Moreover, one-third of the cell lines had low PTEN transcript levels, and 60% of these samples had low or absent PTEN protein, which could not be attributed to gene silencing by hypermethylation. In addition, we found that PTEN and phosphorylated Akt levels are inversely correlated in the large majority of the examined samples. These findings suggest that PTEN plays a role in the pathogenesis of haematological malignancies and that it might be inactivated through a wider range of mechanisms than initially considered. The finding that PTEN levels inversely correlate with phosphorylated Akt supports the hypothesis that PTEN regulates PtdIns(3,4,5)P3and suggests a role for PTEN in apoptosis.

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Section: Dna and Rna Extractionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanismsin haematological malignancies

Dahia

Aguiar

Alberta

et al. 1999

Human Molecular Genetics

255

156

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“…al., 1987). PCR of exons 5-8 was performed as previously described (Aguiar et al, 1995), usng two sets of primers: TGCAGAATTCTG-ACI1TCACTCTGTCTCCT and GATCAAGCITCCAGA-GACCCCAGTTGCAAAC for exons 5 and 6; and GAGCT-CGAGCTCGCGACTGCCTCATCIT and GCATGCGCA-TGCACCCITGGTCTCCTCCAC for exons 7 and 8. The amplification protocol of exon 4 consiste in a denaturation step of 4 min at 94C, followed by 35 cycles at 94'C for 1 min, 55C for 1 min and 72-C for 2 min, and a final 7 mi extension at 72C.…”

Section: Materak and Patientsmentioning

confidence: 99%

Molecular and immunohistochemical analysis of P53 in phaeochromocytoma

Dahia

Aguiar²,

Tsanaclis³

et al. 1995

Br J Cancer

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(Viskochil et al., 1990;Latif et al., 1993; Mulligan et al., 1993), little is known about the moleular pathogeness of the sporadic variants of the tumour. It has been shown that a number of phaeochromocytomas have loss of heterozygosity of chromosome 17p (Khosla et al., 1991). The p53 tumour-suppressor gene, located on this region (17pl3), has been reported as the most frequent genetic abnormality seen in human malignancies (Hollstein et al., 1991). This gene codes for a phosphoprotein that is involved in cell cycle regulation (Lane, 1993; Zambetti and Levine, 1993). Variations in the gene structure that lead to impaired function of the p53 protein may confer genetic instability to the cell, favouring the development of neoplasia (Hollstein et al., 1991).With the aim of detrmining the potential role of p53 in this tumour, we have searched for mutations in a series of phaeochromocytomas using polymerase chain reactionsingle strand conformation polymorphism (PCR-SSCP) analysis of the 'hotspot' region of the gene; the expression of the p53 protein in tumour samples was also assessed by immunohistochemistry. Materak and PatientsWe studied 25 phaeochromocytomas, of which only one was non-functional. The patients' mean age was 31.4 years (range 9-64 years), with tumour size ranging from 4 to 11.5 cm (mean 7.2 cm). Four tumours were ectra-adrenal. Three of the tumours were hereditary, originatig from patients with neurofibromatosis, von Hippel-Lindau disease and familial phaeochromocytoma (without evidence of the complete multiple endocrine neoplasia 2A syndrome); the other 22 were sporadic forms. Twenty-one phaeochromocytomas were benign and four malignant. al., 1987). PCR of exons 5-8 was performed as previously described (Aguiar et al., 1995), usng two sets of primers: TGCAGAATTCTG-ACI1TCACTCTGTCTCCT and GATCAAGCITCCAGA-GACCCCAGTTGCAAAC for exons 5 and 6; and GAGCT-CGAGCTCGCGACTGCCTCATCIT and GCATGCGCA-TGCACCCITGGTCTCCTCCAC for exons 7 and 8. The amplification protocol of exon 4 consiste in a denaturation step of 4 min at 94C, followed by 35 cycles at 94'C for 1 min, 55C for 1 min and 72-C for 2 min, and a final 7 mi extension at 72C. The 25yd reactions contained: 400 PCR-SSCP analysis

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“…However, this could not be confirmed by others. [51][52][53] Similar conflicting results have been reported for the correlation with interferon responsiveness. 54,55 Since a large number of in frame bcr-abl fusions are possible, the number of variant bcr-abl genes leading to functional fusion proteins are in theory vast.…”

Section: The C-abl Genementioning

confidence: 34%