Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A large number of prognostic factors are available to help predict the course of the disease for patients with B-cell chronic lymphocytic leukemia (B-CLL). However, it is not clear the involvement of these well established prognostic factors in the clinical response of the patients with B-CLL to the chemotherapy. The possible association of the patient clinical-biological characteristics and the in vitro response to chemotherapic agents may serve to provide powerful predictive information to identify optimum treatment for patients. An apoptosis induction assay displays the patient in vitro responses to chemotherapy and the possible association with their clinical-biological characteristics. In this study, patients showed a significant better in vitro response to drugs when they were in the initial stages of the disease or with low beta(2) microglobulin serum level. Response to purine analogues was significantly higher in patients with long lymphocyte doubling time (LDT), few cells expressing CD38, normal karyotype or no p53 deletion, whereas there was no correspondence with ZAP-70 expression. Furthermore, a good correlation was shown between in vitro apoptosis induction assay and the patient clinical response to purine analogues. In conclusion, association between in vitro drug sensitivity and some of the markers considered as prognostic factors could help to develop personalised therapeutic regimens for patients with B-CLL.
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PMID:Drug induction apoptosis assay as predictive value of chemotherapy response in patients with B-cell chronic lymphocytic leukemia. 1937 58

Chronic lymphocytic leukemia (CLL) is an incurable disease derived from the monoclonal expansion of CD5(+) B lymphocytes. High expression levels of ZAP-70 or CD38 and deletions of 17p13 (TP53) and 11q22-q23 (ATM) are associated with poorer overall survival and shorter time to disease progression. DNA damage and p53 play a pivotal role in apoptosis induction in response to conventional chemotherapy, because deletions of ATM or p53 identify CLL patients with resistance to treatment. Forodesine is a transition-state inhibitor of the purine nucleoside phosphorylase with antileukemic activity. We show that forodesine is highly cytotoxic as single agent or in combination with bendamustine and rituximab in primary leukemic cells from CLL patients regardless of CD38/ZAP-70 expression and p53 or ATM deletion. Forodesine activates the mitochondrial apoptotic pathway by decreasing the levels of antiapoptotic MCL-1 protein and induction of proapoptotic BIM protein. Forodesine induces transcriptional up-regulation of p73, a p53-related protein able to overcome the resistance to apoptosis of CLL cells lacking functional p53. Remarkably, no differences in these apoptotic markers were observed based on p53 or ATM status. In conclusion, forodesine induces apoptosis of CLL cells bypassing the DNA-damage/ATM/p53 pathway and might represent a novel chemotherapeutic approach that deserves clinical investigation.
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PMID:Forodesine has high antitumor activity in chronic lymphocytic leukemia and activates p53-independent mitochondrial apoptosis by induction of p73 and BIM. 1954 22

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is common in the Western world. Genetic abnormalities detected by fluorescence in situ hybridization (FISH) and immunoglobulin heavy chain variable gene region (IGHV) mutational status are well-known independent prognostic indicators in CLL/SLL. Given the requirement for specialized testing to detect such aberrations, we investigated whether morphologic features may predict the presence of a more or less favorable genetic profile. Forty-one SLL cases were morphologically evaluated for expanded proliferation centers, increased large cells outside of proliferation centers, and nuclear contour irregularities (NCI) in small and large tumor cells. ZAP-70 immunohistochemistry and FISH (deletions of 13q14, p53 and ATM and trisomy 12) were successful in all cases. IGHV mutational status was determined in 26/41 cases. Significant NCI in both small and large cells correlated with the presence of an unfavorable FISH abnormality (ie, ATM or p53 deletions). However, despite good specificity (94%), the sensitivity (57%) of this finding is inadequate for routine use. No other significant associations with morphologic features were identified. Strong ZAP-70 positivity correlated with unmutated IGHV (P=0.001), rendering ZAP-70 IHC a useful surrogate for IGHV mutational status. ZAP-70 positivity predicted against finding a favorable FISH deletion 13q14 (P=0.023). Although we only studied 41 cases, we corroborated their validity using Kaplan-Meier overall survival analysis. In conclusion, morphologic features in SLL are not a reliable predictor of underlying genetic status. Thus, we propose a practical, cost-effective approach to the work-up of these cases, which should be driven by clinical necessity.
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PMID:Most morphologic features in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) do not reliably predict underlying FISH genetics or immunoglobulin heavy chain variable region somatic mutational status. 1982 50

Although chromosome 17p abnormalities and TP53 mutations have been reported as poor prognostic indicators in chronic lymphocytic leukemia (CLL), the impact of aberrant p53 expression as assessed by immunohistochemistry (p53-IHC) has not been defined in patients with CLL treated with chemoimmunotherapy, particularly in the context of other novel markers such as ZAP-70 expression and IgVH mutation status (IgVH MS). We assessed p53-IHC in 222 bone marrow (BM) specimens from patients with CLL enrolled in a phase II trial with fludarabine, cyclophosphamide, and rituximab (FCR). ZAP70 expression and IgVH MS were assessed in 208 and 108 patients, respectively. One hundred sixty-eight patients had concurrent classical cytogenetic analysis. p53-IHC correlated with abnormal karyotype (p = 0.002) and adversely affected overall survival independent of ZAP70 expression and IgVH MS (p < 0.001). Patients with p53-IHC(+) CLL were less likely to achieve complete remission, but patients who did achieve complete remission showed a durable response. In this patient cohort, p53-IHC is an important determinant of complete remission and overall survival, but not remission duration, in patients with CLL receiving FCR.
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PMID:p53 expression by immunohistochemistry is an important determinant of survival in patients with chronic lymphocytic leukemia receiving frontline chemo-immunotherapy. 1970 50

For patients with chronic lymphocytic leukemia (CLL), expression of ZAP-70 in the leukemic cells is an indicator of poor prognosis. However, the mechanism that accounts for this effect is not known. ZAP-70 expression has previously been associated with increased B cell antigen receptor signaling upon surface immunoglobulin ligation in vitro as shown by ZAP-70 and Syk phosphorylation. This finding has led to the suggestion that a more aggressive clinical course is correlated with B cell antigen receptor signaling. Using high resolution immunophenotyping to analyze CLL cells ex vivo (without stimulation in vitro), we have demonstrated CLL cells from all patients express some ZAP-70 and that increased expression of ZAP-70 is correlated with decreased levels of phosphorylated ZAP-70 and phosphorylated Syk measured directly ex vivo. Conversely, high levels of phosphorylated ZAP-70 and phosphorylated Syk are found only in samples with low levels of ZAP-70 expression, and Syk and ZAP-70 phosphorylation appear to be mostly independent of each other. Additionally, Syk phosphorylation is directly correlated with levels of p21(cip1), a cell cycle inhibitor and a p53 target. Together these findings suggest that lower levels of p21(cip1) and/or a defect in p53 activity may account in part for the more aggressive disease course in patients with high levels of ZAP-70 rather than enhanced B cell antigen receptor signaling as has been previously hypothesized.
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PMID:Correlation between ZAP-70, phospho-ZAP-70, and phospho-Syk expression in leukemic cells from patients with CLL. 2001 15

Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder with variable clinical course. Determination of disease prognosis is based on the identification of different prognostic factors. The concept of CLL prognostic factors is still developing and has undergone several fundamental changes. Traditional (old) prognostic factors and staging systems are useful in describing the extent of the disease at any given moment, in determining clinical progression and in the identification of patients who need to start treatment. However, traditional prognostic factors are not sufficient for predicting a long-term prognosis because they are not able to identify potentially aggressive forms of CLL in the early stages. Nevertheless, clinical staging systems maintain their importance and in contrast to other traditional factors also their independent prognostic role. Otherwise, traditional prognostic factors play the role of disease activity descriptors rather than the role of actual prognostic factors. CLL risk profile determination is based on the identification of so-called new prognostic factors, the most relevant of which are chromosomal aberrations, TP53 gene mutations, mutational status of IgVH genes, ZAP-70 and CD38 expression. These factors are able to predict the prognosis already at the time of the initial diagnosis. In contrast to previous ideas, they are not incorporated into recommendations regarding indications for treatment. This is due to the risks associated with early treatment and the lack of data validated in prospective clinical trials demonstrating the justifiability of such procedure. In patients being treated, new prognostic factors may be useful for predicting the response to the therapy and some of them may directly influence the choice of treatment regime. New CLL treatment modalities have also raised the question of their influence on the prognostic and predictive power of new prognostic factors.
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PMID:[Commentary on development of the prognostic factors concept in chronic lymphocytic leukaemia: the route from prognostic factors to therapy response predictors]. 2009 42

The study was purposed to explore the relationship between the expression of deoxycytidine kinase (dCK) gene and fludarabine (Flud) resistance in patients with chronic lymphocytic leukemia (CLL). The real time quantitative polymerase chain reaction (RQ-PCR) technique was used to detect the mRNA expression of dCK gene in the bone marrow or peripheral blood mononuclear cells from 30 CLL patients, the difference of dCK expression levels between CLL patients sensitive to Flud and patients resistant to Flud was analyzed. The results showed that dCK expression level in the Flud-sensitive patients was much higher than that in the Flud-resistant ones (p = 0.001); dCK expression level had no relationship with sex, age, Binet stage, IgVH mutations, CD38, ZAP-70 or p53 gene mutation (p > 0.05). It is concluded that low expression or deficiency of dCK in patients may contribute to resistance against Flud- and the prognostic significance of dCK expression remains to be further studied.
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PMID:[Correlation of deoxycytidine kinase gene expression with fludarabine resistance in patients with chronic lymphocytic leukemia]. 2013 14

Chronic lymphocytic leukemia (CLL) is a monoclonal B-cell malignancy that afflicts mainly older individuals. Since many patients are diagnosed in the earliest stages, the course of the disease may be indolent and asymptomatic, requiring no therapy. For those who are diagnosed in advanced stages or whose disease becomes symptomatic, treatment is indicated. Advances in identifying prognostic factors, such as cytogenetics, IgHV mutational status, CD38, TP53, and ZAP-70, are helping physicians better predict who is more likely to have progressive disease and thus needs more frequent monitoring. Some of these prognostic factors are also helping to guide therapy choices as they can predict response to treatment and/or duration of response. Recent advances in treatment options have moved beyond traditional management with alkylating agents and purine analogs into regimens combining these two chemotherapy classes with monoclonal antibodies targeting CD20. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) has become the most effective therapy option to date for CLL. Compared with fludarabine and cyclophosphamide, FCR has shown higher complete response rates and longer progression-free survival. Bendamustine, a unique alkylating agent with purine analog properties, has recently been approved by the FDA for treatment of CLL and provides a new alternative to existing therapies. Initial trials combining bendamustine with rituximab are showing promise for both untreated and relapsed/refractory disease. Other agents recently approved and/or being tested, such as ofatumumab, flavopiridol, and lenalidomide, are demonstrating activity in the relapsed setting.
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PMID:Chronic lymphocytic leukemia: putting new treatment options into perspective. 2040 96

The diagnosis of chronic lymphocytic leukaemia (CLL) is based on clinical and laboratory features. Morphology and immunophenotype are the initial diagnostic investigations. In atypical cases, these tests should be complemented with molecular genetics and/or histology to exclude other B-cell disorders of small lymphocytes. Morphologically, CLL can be classified into typical and atypical. Immunophenotyping is the only method that can establish or confirm the diagnosis as CLL lymphocytes have a distinct immunophenotypic signature. A scoring system compounding the results with a set of markers allows firming up the diagnosis. Other immunological markers such as CD38 and ZAP-70 have an important prognostic impact. Fluorescence in situ hybridization (FISH) analysis, chiefly by detecting 17p (TP53 locus) and 11q (ATM) deletions and mutational status of the IgVH gene, also provides prognostic information and may determine the type of therapy. In atypical CLL, histology and/or molecular genetics may be required to exclude other B-cell disorders.
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PMID:Diagnostic issues in chronic lymphocytic leukaemia (CLL). 2062 Sep 67

Many prognostic factors have been identified in chronic lymphocytic leukaemia (CLL). Based on the assessment of B cell receptor (BCR) structure and function, a subdivision into subtypes is possible (e.g., immunoglobulin heavy chain variable gene segment (IGHV) unmutated and mutated, V3-21 usage) with distinct biological and clinical characteristics. Recurrent genomic aberrations (i.e., 11q and 17p deletion) and gene mutations (i.e., TP53 and ATM) help to define biological and clinical subgroups. In addition, serum markers (e.g., thymidine kinase (TK) and beta2-microglobulin (beta2-MG)), cellular markers (e.g., CD38 and ZAP70) and clinical staging have an impact on outcome in CLL. The biological characterisation of CLL has not only led to progress in outcome prediction but also has begun to be translated into novel treatment strategies. Nonetheless, most factors associated with prognosis have not been thoroughly interrogated for their predictive value in the light of different therapeutic approaches. With a growing number of agents acting on specific biological targets and being used in different clinical situations, the future is likely to bring the identification of predictive factors in CLL.
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PMID:Moving from prognostic to predictive factors in chronic lymphocytic leukaemia (CLL). 2062 Sep 72


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