Tuesday, November 14, 2006

Del 17p

One of the most feared findings in CLL is a loss of the short arm of chromosome 17. It is usually found by FISH testing and the technical term is del 17p. This stands for a deletion of the 'p' arm (chromosomes have short arms 'p' and long arms 'q')of chromosome 17 (remember there are 46 chromosomes, arranged in 22 pairs -1 to 22 - and the sex chromosomes X and Y). The reason it is feared is because the gene for p53 lives on 17p.

p53 is known as the guardian of the genome. It has many functions, but one of them is to preserve the integrity of genes. In every cell division it is necessary to make a complete copy of the cell's DNA. Each daughter cell has to have a full complement of DNA and it gets it when the parent cell makes a complete copy and hands out one copy to each daughter. The trouble is that this copying process is not as good as Xeroxing; it is a bit error prone. This is where p53 comes in. It zips up the DNA looking for errors and when it finds one it stops the whole factory process and brings in the DNA repair team. These enzymes attempt to repair the error and if they can, all well and good and the process of copying continues. If they can't then p53 sends a signal for the cell to self-destruct. After all you wouldn't want a defective product on your shelves, would you?

Every once in a while the random copying errors affect the p53 gene, so there is nothing to detect and correct the error. These p53 deficient cells are a liability. First of all because they are damaged goods that can accumulate further errors that won't be detected, and some of these errors are liable to make the cell grow at a very fast rate, but second because most of the drugs used to treat CLL require an intact p53 pathway to be able to kill the cell. Only Campath and high dose steroids are able to kill CLL cells that lack p53, although we shall soon have a new drug, flavopiridol that can do this too. So if we lack p53 the cells are liable to divide aggressively and be unkillable.

In recent randomized trials in Germany and the UK about 5% of patients were resistant to treatment with the combination of fludarabine and cyclophosphamide - most died within 2 years of entering the trials. Almost all of these patients had del 17p by FISH.

However in our series of patients in Bournemouth we have three patients with del 17p who have indolent CLL that has never required treatment. How can we explain this?

All three have mutated VH genes. CLL cells with mutated VH genes are almost always only slowly dividing. A missing p53 gene comes about by a rare mistake in cell division. Rare it may be, but it will occur much more commonly in cells that divide rapidly than those that divide slowly. Nevertheless, it can occur in slowly dividing cells. Secondly a missing p53 gene causes havoc when cells divide; if cells divide only slowly there won't be so much havoc.

Therefore, in most patients with del 17p a different treatment strategy is required. Currently we believe such patients should be treated with Campath plus high dose steroids, and once in remission they should proceed to stem cell allograft if possible. However, in patients with indolent disease in whom del 17p is found, a watch and wait policy should be adopted.

Although the incidence of del 17p is less than 5% in untreated patients, it is much higher, perhaps up to 30% in relapsed patients. Why is this? It is because the CLL cells that recover after chemotherapy are the ones that were most resistant to treatment the first time around. The best known cause of drug resistance is p53 deficiency. For this reason many people think that it is important to avoid treatment in CLL until it is really necessary.

6 comments:

Georeg E Deichert said...

Dr. Hamblin,

Is the entire short arm of p17 deleted, or is the p53 gene just one of many locations (or loci) on that arm?

Thanks for you help to all CLLers.

George

Terry Hamblin said...

No, it is part of the short arm, but more than just the p53 gene. But you need full karyotyping to know that. FISH only looks at the p53 gene.

Anonymous said...

How do you test for the 17p deletion? On bone marrow sampling or by a blood test?

Terry Hamblin said...

It's done on a blood test.

Brian Koffman said...

I understand that del 11q is also harder to treat. Is Rituxan an option for del 11q?

Martina Barthov√° said...

Del17p is usually monoallelic. Do you agree? If it is monoallelic,is the second allele always mutated?
Does del17p always mean lack of p53 or only in the majority of cases?

Thanks for your excellent web page.

Martina