Stereotypy and CLL

Although some are obsessed with finding surrogates, I still support the test for IGHV mutations as one of the best prognostic markers for CLL. CD38, ZAP-70 and CD 49d all have their advocates, but each has its drawbacks and the only thing in favor of them is that most labs now have a flow cytometer. However, a gene sequencer is no more expensive to buy and the sequencing of IGHV genes has became a largely automated test. I saw a paper the other day which had collected gene sequences from over 8000 CLL patients.

There have been developments in IGHV testing that have made it a much more interesting tool. They can be summed up by the word 'stereotypy'.

When I first stared talking to Nick Chiorazzi about IGHV genes he told me about five sequences he had determined from patients who originated from all over the world. They had all used the same IGHV gene, V4-39, and they all had surface IgG rather than IgM+D. Furthermore they all had the same Ig sequence. Since there are a possible thousand billion different sequences, it was difficult to believe that there hadn't been some cross contamination. But Nick assured me that they had checked for this and the identity was confirmed.

Then Gerrard Tobin and Richard Rosenquist produced the astonishing finding that patients whose CLL used the V3-21 gene had a poor prognosis whether they were mutated or unmutated. When I saw the sequences it became clear that many of the V3-21 had identical or near-identical sequences. It all suggested that at least for some CLLs the leukemia had originated in a clone of B lymphocytes that was expanding in response to stimulation by a single antigen.

The question then was, if there are these two families of cases with identical sequences, are there others? Enter Kostas Stamatopoulos from Greece. In collaboration with workers in many countries he has established that approximately one patient in three has a IGHV sequence that belongs to a stereotyped family. Moreover for some of these there is a clinical correlation - all members of the family behave similarly, and the originating antigen has been determined. For some of the families the members are too few for us to be accurate about how they will behave, which provides a justification for everybody to have their V genes sequenced. Sequences that were near-identical for a number of patients were given the name 'stereotypes'.

Here are some examples:
Stereotype #2 V3-21 mutated or unmutated, poor prognosis, antigentic stimulation by coffin-1, high frequency del 11q23.
Stereotype #8 V4-39, unmutated, surface IgG, poor prognosis, antigenic stimulation by vimentin, 17 fold risk of Richter's transformation, high frequency of trisomy 12.
Stereotype #4 V4-34, mutated, good prognosis, presentation at young age (~43), antigenic stimulation by Ii blood group.
Stereotype #16 V4-34, mutated, good prognosis - though not as good as #4.
Stereotype #1 V1-5-7, unmutated, poor prognosis, antigenic stimulation by vimentin.
Stereotype #5 V1-69, umutated, antigenic stimulation by coffin-1, favorable prognosis.
Stereotype #6 V1-69, unmutated, antigenic stimulation by non-muscle myosin heavy chain, prognosis intermediate.

It can be seen that family identity over-rides both the particular V gene used and the mutational status. There is obviously a lot more to come from this approach.