I e-mailed Lou Staudt when I saw his paper before it was published and asked him to come to England and talk about it. He seemed pleased to hear from me. We had not met previously but our work had suddenly become complimentary. The prognosis was so different between mutated and unmutated CLL that the question had to be asked whether they were both the same disease. Lou had developed his Lymphochip as a way of looking at which genes were switched and which switched off in a particular tissue. He had already explored the complexity of diffuse large cell lymphoma and it was an obvious move to look at CLL. His results clearly showed that CLL was a single disease very different from any other lymphoma and different also from most types of B cell.
What I didn’t understand was why it took so long to get published. We knew that it had been circulating around high impact journals and it was obviously a very important paper. We began to think that dark forces were preventing its publication.
Publication ethics is a can of worms. Referees are on their honor to say if they have a competing interest. Authors should reveal whether the paper has been published before in part or whole. Editors should not employ chicanery to raise their impact factor. All have sinned and fallen short of the glory of God.
When it was published it was brilliant. It identified a number of genes which separated the mutated and unmutated subset. Most important of these was ZAP-70. This could have been easily missed because it is always switched on in T cells, so unless the T cells had been depleted from the CLL specimens it would not have been found.
Lou couldn’t make the meeting, but Andreas Rosenwald (who is about 7ft tall) came instead and there began a useful collaboration. We began to develop tests for ZAP-70 and by 2002 we had a working flow cytometry test that remains our benchmark assay.
Emili Montserrat’s group in Barcelona developed a very similar test, again ready for the 2002 ASH meeting, and then last year Tom Kipps’ group working with the CLL Consortium developed a single step flow assay that can be used on whole blood.
Guess what? Concordance with VH genes isn’t perfect, and in fact with some assays it is hardly better than CD38.