Wednesday, November 17, 2010

Del 13q14 - the Bournemouth background

I feel a sort of ownership for del 13q14, since it was on some of my patients that the first cases in both CLL and myeloma that it was discovered in 1987. The paper was a collaboration between my colleague David Oscier and Marina Seabright,in nearby Salisbury, who had discovered Trypsin banding of chromosomes, a discovery that opened up the localization of genes on chromosomes. David went on to do a great deal of work on del 13q14 in CLL, including showing that it had a good prognosis and that most cases had mutated IGVH genes .

At first we thought it must be related to a tumor suppressor gene – there was already a known tumor suppressor, Rb1, at 13q12. So David set about finding the minimally deleted region on 13q14 and sequencing the genes that could be found there. Unfortunately, the link with the Salisbury lab was broken at the time as Marina Seabright retired, and her successor, though an esteemed scientist and FRS had little or no interest in leukemia and transferred the research funds to a pet project of her own involving the fragile X chromosome. She was within her rights to do this but it disappointed us. Luckily I was able to find internal money from my own budget and employ three experienced cytogeneticists from Salisbury so that we could establish our own chromosome lab in Bournemouth. Since this move has generated over 60 publications we can’t say it was regrettable, but we are pleased to say that now Nick Cross has been appointed to Salisbury, the link has been re-established and had has been very profitable to science.

New collaborations were set up with the Karolinska in Stockholm and with the Vavilov Institute of General Genetics, Moscow. It was strange that David had to go abroad to establish these collaborations, but I seem to remember an attempt to set up a British collaboration, where the potential collaborator’s view of ‘collaboration’ was more akin to ‘commandeering’ and that attempt was abortive.

By 1998 these collaborations had produced a molecular map of the minimally deleted area and had identified three genes, Leu1, Leu2, and Leu5 within the minimally deleted area. None of these genes were translated as protein and none seemed to be tumor suppressor genes. If you remember this was the time of all the razzmatazz about the Human Genome Project when the big surprise was how few genes there seemed to be controlling our bodies – nearer to 30,000 than the expected 100,000. So the search turned to genes that controlled expression of protein rather than those that translated it.

This was where the big boys stepped in. There was sufficient interest in this subject and by 2001 both Columbia New York and Philadelphia had re-sequenced the minimally deleted area and confirmed our work. Then in 2002 Carlo Croce and George Calin discovered the missing miR genes on the deleted site and suggested that these were allowing an over expression of bcl-2, a known problem in CLL.

I quote from their paper, “Micro-RNAs (miR genes) are a large family of highly conserved noncoding genes thought to be involved in temporal and tissue-specific gene regulation. MiRs are transcribed as short hairpin precursors (≈70 nt) and are processed into active 21- to 22-nt RNAs by Dicer, a ribonuclease that recognizes target mRNAs via base-pairing interactions.”

It all seemed settled here, but then it all got more complex as it became clear that del 13q14 didn’t mean that everything in the garden was rosy for everybody. Some of the problems were straightforward. We had always said that it was only isolated del 13q14 that had the favorable prognosis; any accompanying abnormality trumped it. We had also made it clear that having unmutated IGVH genes called the whole party off; they also trumped it. Our own careful studies had also revealed that del 13q14 was much commoner than had been published; most studies had suggested that up to 50% of CLL cases had the missing section, but when we looked carefully we found that there were translocations that had lost a small porting of 13q and other very small interstitial deletions that had lost small parts of the critical region. It was clear that some part of 13q was involved in CLL in over 80% of cases.

Then there were clinical questions. What about when both chromosome 13s had lost parts? One paper suggested that this carried a worse prognosis, but our own data did not support this. Were there any differences if a large part of the chromosome was missing compared with a small part?

Thankfully, answers are beginning to emerge, and there are papers at ASH this year that address the problem.

I think that that is all I am going to write today. I shall bring you all an update in a short while to explain how things are now.

3 comments:

George said...

Huge credit and respect to Nick Cross....
Latest data re biallelic del(13)? cancels out, improves or doesn't affect at all over single deletion?

Terry Hamblin said...

Wait and see!

Debboe said...

Anxiously waiting.