History of CLL (Part 5)

To the end of the Millennium

Today, we think of diseases in terms of molecules. Our molecular understanding of CLL is incomplete. It had a poor start. It was not until 1979 that the first consistent chromosomal abnormality (trisomy 12) was reported (Gahrton et al, 1979). We still do not know what it means. The translocations t(11;14)(q13;q32) and t(14;18)(q32;q21) involving the supposed B-cell leukaemia oncogenes BCL-1 and BCL-2 proved to relate mainly to what the ancients called lymphosarcoma cell leukaemia. Translocations at t(14;19)(q32;q13) involving BCL-3 (Ueshima et al, 1985)do occur in CLL, but are vanishingly rare. The commonest abnormality involves deletions at 13q14 (Fitchett et al, 1987) and its unravelling has thrown up candidate genes
that might be responsible for most cases (Liu et al, 1997). An important subset of more malignant cases and bulky lymphadenopathy has deletions at 11q23 (Dohner et al,
1997). As with most tumours, p53 is involved somewhere (Lens et al, 1997) and not to the advantage of the patient.

A new and important cell marker, CD79b, is surprisingly absent, although probably present as a short splice variant (Alfarano et al, 1999). This has been included in a cell marker definition of the disease that is remarkably helpful (Moreau et al, 1997).

We no longer consider CLL to be a disease of accumulation of long-lived functionally incompetent lymphocytes. We prefer to describe the cells as anergic, activated and
antiapoptotic (Caligaris-Cappio, 1996; Caligaris-Cappio & Hamblin, 1999), which comes to much the same thing. But in another respect, David Galton was right. He described two types of CLL, one progressive and one stable. This can also
be translated into molecular parlance. By studying the immunoglobulin variable (V) region genes, we can discern the same two distinct types. One type, derived from a naive cell (recognized by having unmutated V genes), is progressive with a median survival of 8 years. The other type, derived from a memory cell (recognized by having mutated V genes), is stable with a median survival of 25 years (Damle et al, 1999; Hamblin et al, 1999).

What is remarkable about the study of CLL is how often the great doctors of the past have been scintillatingly right. What is comforting is how often they have been
spectacularly wrong.

This review was written in the last year of the last century and is published in the British Journal of Hematology 2000, 111, 1023-1034. It probably needs updating, but almost all of what has happened subsequently is published wlsewhere on this blog.

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