A novel functional assay using etoposide plus nutlin-3a detects and distinguishes between ATM and TP53 mutations in CLL

Best, O. Giles; Gardiner, Anne; Majid, Aneela; Walewska, Renata; Austen, Belinda; Skowrońska, Anna; Ibbotson, Rachel; Stankovic, Tatjana; Dyer, Martin J. S.; Oscier, David

doi:10.1038/sj.leu.2405092

Cited by 58 publications

(50 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In a separate study, category 1 dysfunction was shown to be confined to patients with TP53 mutation. 5 Six of the seven patients tested had category 1 TP53 dysfunction. Only one patient (patient 6) had evidence of TP53 loss without either a mutation in the remaining allele or TP53 dysfunction ( Table 1).…”

mentioning

confidence: 95%

See 1 more Smart Citation

A subset of Binet stage A CLL patients with TP53 abnormalities and mutated IGHV genes have stable disease

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

mentioning

confidence: 95%

“…Direct sequencing for TP53 gene mutations in exons 5-9 was carried out as described previously. 5 The median follow-up from the time of mutational analysis was 63 months. TP53 mutations were identified in six of the seven samples tested.…”

mentioning

confidence: 99%

A subset of Binet stage A CLL patients with TP53 abnormalities and mutated IGHV genes have stable disease

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…A simple in vitro test based on comparing p53 upregulation and p53-dependent gene expression in CLL cells treated with the genotoxic agent etoposide and with nutlin readily distinguishes between patients with an intact p53 system, with dysfunctional p53 or dysfunctional ATM, respectively. 60 This test may be of value in selecting patients resistant to cytotoxic drugs by virtue of Atm dysfunction, and who may therefore benefit from nutlin treatment. However, a potential pitfall in the clinical use of nutlin is that treatment with this agent may encourage the selection and expansion of p53-mutant clones, which would be difficult to eliminate by existing therapeutic agents.…”

Section: Non-genotoxic Agents That Upregulate P53mentioning

confidence: 99%

p53 and Notch signaling in chronic lymphocytic leukemia: clues to identifying novel therapeutic strategies

2011

View full text Add to dashboard Cite

The p53 tumor suppressor protein has a key role in the induction of apoptosis of chronic lymphocytic leukemia (CLL) cells. Abnormalities within the p53 pathway identify a subset of patients with a poor prognosis. This review describes recent advances in understanding the mechanisms that regulate p53 levels and the role of p53 in the control of the cell cycle and of apoptosis. The classical model of p53-mediated apoptosis emphasizes the transcriptional activation of proapoptotic genes. In contrast, a novel model emphasizes p53's non-transcriptional actions as the major route of apoptosis induction, whereas its transcriptional arm predominantly upregulates antiapoptotic genes, thus providing a negative feedback mechanism that limits apoptosis. Further studies have identified the Notch pathway as a candidate p53-induced antiapoptotic mechanism. In contrast to the classical model, the novel model predicts that pharmacological inhibition of p53's transcriptional function or of the Notch signaling pathway will augment apoptosis induction by cytotoxic agents. Therapeutic strategies based on the novel model, which we review here for the first time, may significantly augment the antitumor actions of cytotoxic agents in CLL and in other malignancies.

show abstract

“…[27][28][29] A recent study found a good relation between FACS abnormalities and 17p deletions in 8 patients, but also revealed a certain amount of heterogeneity and discordance among patients with the 11q deletion, 30 suggesting that the precise correlation of 17p deletions, 11q deletions, and particularly TP53 mutations, with the p53/p21 assay is currently unclear. A recent report added another layer of complexity by suggesting an association between single-nucleotide polymorphisms in the p21 gene with impaired p21 up-regulation and intact p53 induction.…”

Section: Introductionmentioning

confidence: 99%

DNA damage–induced transcriptional program in CLL: biological and diagnostic implications for functional p53 testing

Mohr

Helfrich

Fuge

et al. 2011

Blood

View full text Add to dashboard Cite

The DNA damage pathway plays a central role in chemoresistance in chronic lymphocytic leukemia (CLL), as indicated by the prognostic impact of TP53 and ATM loss/ mutations. We investigated the function of the p53 axis in primary CLL samples by studying p53 and p21 responses to irradiation by FACS and RT-PCR. We observed a distinct response pattern for most cases with a 17p deletion (n ‫؍‬ 16) or a sole TP53 mutation (n ‫؍‬ 8), but not all cases with a p53 aberration were detected based on a number of different assays used. Samples with a small clone with a TP53 mutation remained undetected in all assays. Only 1 of 123 cases showed high expression of p53, which is suggestive of p53 aberration without proof of mutation of TP53. Samples with an 11q deletion showed a heterogeneous response, with only 13 of 30 showing an abnormal response based on cutoff. Nevertheless, the overall induction of p53 and p21 was impaired, suggesting a gene-dosage effect for ATM in the 11q-deleted samples. The detectability of p53 defects is influenced by clonal heterogeneity and sample purity. Functional assays of p53 defects will detect a small number of cases not detectable by FISH or TP53 mutational analysis. The clinical utility of functional p53 testing will need to be derived from clinical trials. (Blood. 2011;117(5): 1622-1632)

show abstract

A novel functional assay using etoposide plus nutlin-3a detects and distinguishes between ATM and TP53 mutations in CLL

Cited by 58 publications

References 7 publications

A subset of Binet stage A CLL patients with TP53 abnormalities and mutated IGHV genes have stable disease

A subset of Binet stage A CLL patients with TP53 abnormalities and mutated IGHV genes have stable disease

p53 and Notch signaling in chronic lymphocytic leukemia: clues to identifying novel therapeutic strategies

DNA damage–induced transcriptional program in CLL: biological and diagnostic implications for functional p53 testing

Contact Info

Product

Resources

About