P53(TP53)/ATM Probe Combination
- P53, 17p13.1, Red
- ATM, 11q22.3, Green
The P53 probe is 161kb, labelled in red and covers the whole P53 gene, extends 66kb telomeric to the gene and covers a region centromeric to the gene, to just beyond the marker D17S655. The ATM probe is 182kb, labelled in green, and covers the telomeric end of NPAT gene and the centromeric end of the ATM gene to just beyond the D11S3347 marker.
Although previously difficult to detect, the advent of FISH analysis of interphase cells from patients with B-CLL showed that around 17% of patients with the disease have deletions of the P53 (TP53) gene1. As with ATM, deletions of P53 have important therapeutic implications for patients with B-CLL2.
Knowledge of the P53 deletion status in the patient should mediate the choice of therapy. P53 is a tumour suppressor gene and its protein product is responsible for the death of cells that contain damaged DNA. This is thought to be brought about by phosphorylation of P53 and the subsequent prevention of its repression by MDM2 (Mouse Double Minute 2 Homolog). This phosphorylation is mediated by ATM. In the absence of P53 activity, cells that cannot be repaired by ATM will continue to proliferate in their damaged state. Patients deleted for P53 may be rendered resistant to alkylating chemotherapeutic agents3 and purine analogues4 as these are designed to damage DNA in the cells that P53 would have destroyed. In the absence of P53, therefore, patients treated with these agents will harbour a proliferating population of damaged cells.
The protein kinase ATM (Ataxia-Telangiectasia Mutated) gene, located in 11q22.3, is frequently deleted in cases of B-CLL. ATM is an important checkpoint gene involved in the management of cell damage and its function is to assess the level of DNA damage in the cell and attempt repair by phosphorylating key substrates involved in the DNA damage response pathway. The ATM/P53 interaction in B-CLL has been shown to play an important role in the proliferation of lymphoid cancer5. It has been shown that ATM concurrently enhances the phosphorylation of P536, should the damage be so great that the cell requires destruction by apoptosis (which is mediated by P53). Deletion of ATM removes this checkpoint activity and hence activation of P53. Thus, there is no attempt made to repair or to apoptose damaged cells, despite the presence of P53. In the absence of ATM, damaged cells are allowed to continue to proliferate.
Screening for deletions of ATM and/or P53 is vital to allow informed therapy choices for CLL patients, especially as deletions of P53 and ATM confer poor prognosis2.
The quality of the products we have received from Cytocell have been excellent. The FISH probes they provide to us give intense, strong signals and are a pleasure to count. What has really stood out however has been the level of support and assistance provided by Cytocell’s application specialists. The team worked very closely alongside our own during the adoption of this product and spent many hours with us perfecting the technique, going above and beyond what I would expect during the transition period. Source BioScience absolutely demand high quality products and service to be able to deliver our results with confidence, and that is what we have received from Cytocell. Neil Ryan, Laboratory Operations Manager at Source BioScience
1. Döhner et al., J Mol Med 1999;77:266-81
2. Foá et al., Haematol 2013; 98(5):675-685
3. Sturm et al., Cell Death Differ. 2003 Apr;10(4):477-84
4. Döhner et al., Blood. 1995 Mar 15;85(6):1580-9
5. Stankovic et al., Blood 2004;103(1):291-300
6. Khanna et al., Nature Genetics 1998;20(4):398-400
- Area of Interest*
This product is intended to be used on Carnoy’s solution (3:1 methanol/acetic acid) fixed haematological samples.
*Disease information supported by the literature and is not a reflection of the intended purpose of this product.