ABL – a Leukemia Gene in a New Context

This week I once again decided on a gene classic. This classic, however, has just been described in a new context. But first, the already well established connection between this gene and a particular form of leukemia leads us back to the early 1960s. It was during these medically exciting years – in which the birth control pill, for example, made its revolutionary introduction – that for the first time a strange-looking chromosome was associated with a severe form of leukemia, chronic myelosis. This strange chromosome was named the Philadelphia chromosome after the location of the first discovery.

It was not until 1973 that researchers succeeded in explaining how this atypical chromosome comes about: it is a so-called translocation in which a piece of the short arm of chromosome 9 changes places with part of the long arm of chromosome 22 (see picture).

In order to understand how this translocation can cause leukemia, the area at the breakpoint of both chromosomes had to be examined more closely. The area on chromosome 22 was simply called the breakpoint cluster region (BCR) for pragmatic reasons. The gene product which is normally encoded by this sequence is of so minor importance that I will save further explanations. The gene located on chromosome 9 exactly in the area that lies adjacent to the BCR of chromosome 22 after the translocation, has the rather cumbersome name Abelson murine leukemia viral oncogene homolog 1, or ABL1 for short. ABL1 is a so-called tyrosine kinase: this is a protein that can attach phosphate groups to other proteins.

For the cell, these special phosphate groups are a signal for the initiation of cell division. The expression of ABL1, is therefore strictly controlled and usually only takes place where such a division is desirable. The translocation between chromosomes 9 and 22, however, creates a new gene that is created from the fusion of the two areas at the breakpoints and is thus called BCR-ABL. As a result, ABL1 escapes the control under which it is normally on chromosome 9 and instead is active permanently. So it constantly sends the signal for cell division, which is fatal in most tissues of an adult organism. White blood cells are particularly responsive to this signal, which causes them to divide uncontrollably. In fact, over 95% of chronic myeloses (also chronic myeloid leukemia, or CML) are based on such a Philadelphia chromosome.

Protein Kinase Inhibitors – A Success Story of the Pharmaceutical Industry

There are a lot of really bad stories in the orbit of the pharmaceutical industry. However, a number of significant medical advances that were initiated by pharmaceutical giants cannot be denied. The history of protein kinase inhibitors is one such success story. Until the 1990s, the therapeutic approaches against CML were rather noneffective. Besides interferon therapy, which at the cost of severe side effects usually only resulted in a short increase in survival time, there was only the option of a bone marrow transplant. However, this was associated with a rather modest success rate and high mortality.

Since it had been clear for several years that it was only the single BCR-ABL protein that caused the disease, in the late 1980s there was an intensive search for substances that specifically inhibit the activity of this kinase. In the 1990s, the time had come and researchers at Ciba-Geigy (later Novartis) discovered a small molecule that binds directly in the active center of the BCR-ABL protein (and only there!) and inhibits the activity of the kinase (see image). In 1998, the first clinical studies were finally carried out and only 3 years later, after a relatively extremely short period of time, Imatinib (sold under the name Gleevec) was approved by the Food and Drug Administration in 2001. This resulted in remission in no less than about 90% of patients. To date, most cases of CML can be treated very well with this small molecule.

A completely different role for ABL

Last week there was news about ABL. However, these have nothing to do with leukemia. Researchers at Baylor College of Medicine in Houston have genetically examined some patients with congenital heart defects, skeletal malformations, and developmental delays. Most of these patients would have been misdiagnosed with Marfan’s syndrome. However, this syndrome is based on a completely different mutation. In fact, the researchers found a mutation in ABL1 that increases the activity of the tyrosine kinase. And now comes the sentence with which I have to close many of my articles: We do not yet know the mechanism underlying the fact that in this case too high ABL activity triggers a developmental disorder and not leukemia.