Expression of p53 and retinoblastoma gene in high‐grade nodal peripheral T‐cell lymphomas: immunohistochemical and molecular findings suggesting different pathogenetic pathways and possible clinical implications

Pescarmona, Edoardo; Pignoloni, Patrizia; Santangelo, Carmela; Naso, Giuseppe; Realacci, Massimo; Cela, Olga; Lavinia, Anna Maria; Martelli, Maurizio; Russo, Matteo Antonio; Baroni, Carlo D.

doi:10.1002/(sici)1096-9896(199908)188:4<400::aid-path379>3.0.co;2-#

Cited by 14 publications

(9 citation statements)

References 44 publications

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“…As expected, Mdm2 was expressed only in a fraction (30.8%) of p53 positive cases and in none of the p53 negative cases: interestingly, in a recent study, we have already investigated at molecular level 9 out of the 13 p53 positive cases of nodal PTCL reported here, showing in all nine cases the presence of a non‐mutated (wild‐type) p53 protein17. Thus, the over‐expression of Mdm2 may account for p53 over‐expression in four of these cases18; p53 over‐expression in the remaining cases needs still to be explained.…”

Section: Discussionsupporting

confidence: 81%

p53 over‐expression identifies a subset of nodal peripheral T‐cell lymphomas with a distinctive biological profile and poor clinical outcome

Pescarmona

Pignoloni

Puopolo

et al. 2001

The Journal of Pathology

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Peripheral T-cell lymphomas (PTCL) are usually characterized by aggressive clinical behaviour and poor clinical outcome, but their biological background has not been extensively investigated to date, due to their low incidence, about 10% of all non-Hodgkin's lymphoma cases in Western countries, and also to the paucity of specific molecular-genetic abnormalities. Neverthless, there is increasing biological and clinical evidence that primary nodal PTCL should be considered separately from extra-nodal cases, but little is known about biological factors of possible clinical and prognostic impact. This immunohistochemical study has analysed the expression of p53, Mdm2, p21(WAF1), BCL-2 and p-glycoprotein (MDR-1 gene product) in a series of 45 cases of nodal peripheral T-cell lymphomas (PTCL) with 'high-grade' histology. The immunohistochemical findings were then correlated with proliferative activity and clinical outcome. p53 was over-expressed in 13 cases (28.9%). p53 positive cases showed significantly higher proliferative activity (p<0.01), more frequent expression of Bcl-2 (p<0.01) and less frequent expression of p21(WAF1) than p53 negative cases. Mdm2 and p-glycoprotein were expressed in 4/13 (30.8%) and 8/13 (61.5%) p53 positive cases respectively, and in none (0%) of the p53 negative cases (p<0.01). Analysis of the survival curves showed that p53 positive cases were associated with a significantly poorer clinical outcome than p53 negative cases, in terms of both overall survival (p=0.0032) and event-free survival (p=0.0004). Furthermore, multivariate analysis showed that p53 expression was the most important independent prognostic variable. These findings indicate that p53 over-expression identifies a subset of nodal PTCL cases with a distinctive biological profile (higher proliferative activity, less frequent expression of p21(WAF1) and more frequent expression of Bcl-2, Mdm2 and p-glycoprotein than p53 negative cases) and poor clinical outcome. The immunohistochemical analysis of p53 expression is a simple, rapid and low-cost method which may provide information of potential clinical and prognostic value in nodal peripheral T-cell lymphomas.

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Section: Discussionsupporting

confidence: 81%

p53 over‐expression identifies a subset of nodal peripheral T‐cell lymphomas with a distinctive biological profile and poor clinical outcome

Pescarmona

Pignoloni

Puopolo

et al. 2001

The Journal of Pathology

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“…Others have not identified p53 gene mutations in peripheral T-cell lymphomas. 23 The high frequency of p53 expression in high-grade T-cell lymphomas including ALCL, and the low frequency of p53 gene mutations suggest that mechanisms other than p53 gene alterations stabilize the wild-type p53 gene product. The presence of wild-type p53 in most ALCL tumors is further supported by our results showing that a p53-induced gene, p21, 24 is expressed in a subset of ALCL tumors (Table 2 and Figure 4), suggesting that p53 protein is capable of inducing expression of target genes.…”

Section: Discussionmentioning

confidence: 99%

p53 gene mutations are uncommon but p53 is commonly expressed in anaplastic large-cell lymphoma

et al. 2005

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Anaplastic large-cell lymphoma (ALCL), as defined in the World Health Organization, is a heterogeneous category in which a subset of cases is associated with the t(2;5)(p23;q35) or variant translocations resulting in overexpression of anaplastic lymphoma kinase (ALK). p53 has not been assessed in currently defined subsets of ALCL tumors. In this study, we assessed ALK þ and ALKÀ ALCL tumors for p53 gene alterations using PCR, single-strand conformation polymorphism and direct sequencing methods. We also immunohistochemically assessed ALCL tumors for p53 expression. Three of 36 (8%) ALCL tumors (1/14 ALK þ , 2/22 ALKÀ) with adequate DNA showed p53 gene mutations. By contrast, p53 was overexpressed in 36 of 55 (65%) ALCL tumors (16 ALK þ , 20 ALKÀ). p21, a target of p53, was expressed in 15 of 31 (48%) ALCL tumors including seven of 15 (47%) p53-positive tumors. p21 expression in a subset of ALCL suggests the presence of functional p53 protein. Apoptotic rate was significantly higher in p53-positive than p53-negative tumors (mean 2.78 vs 0.91%, P ¼ 0.0003). We conclude that the p53 gene is rarely mutated in ALK þ and ALKÀ ALCL tumors. Nevertheless, wild-type p53 gene product is commonly overexpressed in ALCL and may be functional in a subset of these tumors.

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“…Immunostaining for caspase was evaluated as clear when staining was as intense as that of the positive internal control, and clearly positively stained cells were judged to be caspase-positive. According to the percentage of caspase-positive cells, immunostaining results were semiquantitatively scored as follows: 0, when absent; 1ϩ, when Ͻ10% of cells in the field were positive; 2ϩ, when 10% to 50% of cells in the field were positive; 3ϩ, when Ͼ50% of cells in the field were stained (Pescarmona et al, 1999). Substitution of normal serum for primary antibodies, Induction of apoptosis in KFB lines after serum deprivation.…”

Section: Immunoreactivity Scoringmentioning

confidence: 99%

Enhanced Expression of Caspase-3 in Hypertrophic Scars and Keloid: Induction of Caspase-3 and Apoptosis in Keloid Fibroblasts In Vitro

Akasaka

Ishikawa

Ono

et al. 2000

Laboratory Investigation

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SUMMARY:Recent studies have suggested that the regulation of apoptosis during wound healing is important in scar establishment and development of pathological scarring. To examine the phenomenon of apoptosis and its involvement in the process of pathological scarring, we immunohistochemically quantified differential levels of expression of caspase-3 and -2, which are activated during apoptosis in vitro, in surgical resected scar tissues. We divided 33 cases of normally healed flat scars and 18 cases of pathological scars (15 cases of hypertrophic scars and 3 cases of keloid) into three groups (S1 ϭ Ͻ10 months' duration; S2 ϭ 10 to 40 months' duration; and S3 ϭ Ͼ40 months' duration) according to the duration of scar. In all three groups examined, the semiquantitative scores for caspase-3 staining were significantly higher for the combination of hypertrophic scars and keloid as a group compared with normally healed flat scars, suggesting reduced cell survival and increased apoptotic cell death in hypertrophic scars and keloid. Apoptosis and caspase proteolytic activities were examined in vitro using two flat scar-derived fibroblast lines (FSFB-1 and -2) and two keloid-derived fibroblast lines (KFB-1 and -2). After 24 hours of serum deprivation, apoptotic cells were significantly increased in both KFB lines, whereas serum deprivation of FSFB-1 cells did not result in a significant increase in apoptotic cell number. After serum deprivation, significant increases in caspase-3 proteolytic activities were detected in both KFB lines compared with both FSFB lines. In contrast, no significant differences with caspase-8 activity were observed between similarly treated KFB and FSFB lines. Furthermore, serum deprivation-induced apoptosis of KFB-2 cells was significantly inhibited by the caspase-3 inhibitor Ac-Asp-Glu-Val-Asp-fluoromethyl ketone (DEVD-FMK), indicating that caspase-3 is important for serum deprivation-induced apoptosis in KFB-2 cells. Considering the role of caspase-3 as a key effector molecule in the execution of apoptotic stimuli, our results suggested that enhanced expression of caspase-3 in hypertrophic scars and keloid induces apoptosis of fibroblasts, which may play a role in the process of pathological scarring. (Lab Invest 2000, 80:345-357).

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Expression of p53 and retinoblastoma gene in high‐grade nodal peripheral T‐cell lymphomas: immunohistochemical and molecular findings suggesting different pathogenetic pathways and possible clinical implications

Cited by 14 publications

References 44 publications

p53 over‐expression identifies a subset of nodal peripheral T‐cell lymphomas with a distinctive biological profile and poor clinical outcome

p53 over‐expression identifies a subset of nodal peripheral T‐cell lymphomas with a distinctive biological profile and poor clinical outcome

p53 gene mutations are uncommon but p53 is commonly expressed in anaplastic large-cell lymphoma

Enhanced Expression of Caspase-3 in Hypertrophic Scars and Keloid: Induction of Caspase-3 and Apoptosis in Keloid Fibroblasts In Vitro

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