A UCD research team has made a mouse model that will allow a fatal form of leukaemia to be studied, writes Dick Ahlstrom
Our ability to study a deadly form of leukemia has been transformed following the development of a mouse that duplicates the uman disease. It will allow a detailed study of how the disease occurs but also provides a way to identify drugs that can stop the disease.
The research project that created the transgenic mouse was designed and managed at University College Dublin by the director of the National Virus Reference Laboratory and professor in the school of medicine and medical sciences, William Hall.
It focused on an invariably fatal form of leukemia known as Adult T-cell Leukemia-lymphoma (ATLL). It is caused after infection with a human virus known as HTLV-1, Hall explains.
"The virus infects about 20 million people world wide, mainly in Africa, the Caribbean, South America and particularly Japan. Most people with the infection don't get the disease but between 2 and 5 per cent will get this aggressive ATLL leukemia," he says.
The disease is often passed on to the developing foetus or soon after birth in breast milk, he states. Studying the disease has been a challenge however because it has a latency period after infection of between 20 and 60 years.
Research had shown that the disease, which is still little understood, is linked to a cancer promoting protein in the virus called Tax. This "oncoprotein" can on exposure transform T-cells to become cancerous cells and initiate ATLL disease.
With this in mind and realising that researchers desperately needed a model that would help the study of the disease, Hall got his postdoctoral research fellow Hideki Hasegawa and others working on the development of a transgenic mouse. They described their work last month in the journal Nature Medicine.
They isolated the gene responsible for Tax and transferred this into the mouse. "The key thing is you have to control expression of the gene and you do this using a promoter," explains Hall.
The gene promoter used by Hall blocks all expression in the mouse except in the thymus gland located in the chest. This was chosen because the immune system's T-cells mature when they pass through the thymus and it is here they are transformed by the Tax oncoprotein if it is present.
The resultant transgenic mouse performed very well and matched the disease progression seen in humans, Hall states. "The gene was switched on in the thymus, transformed T-cells and caused an identical disease." It even caused the additional opportunistic diseases seen in humans whose immunocompromised T-cells can no longer defend against them.
The mouse mimicked the disease a little too well however in having a long latency period. "We had a perfect model identical to the human disease but it was still taking 10 to 20 months to develop," Hall explains.
To accelerate the disease they decided to transfer some of the cancerous transformed T-cells from their mouse into another strain of mouse with severe combined immunodeficiency, known as SCID mice.
This last step provided them with a model that develops ATLL identical to that seen in humans but the disease emerges in only four weeks. At last the researchers have a model for the disease that will allow a full-blown assault on tackling this form of leukemia and perhaps others. "We will now be able to look at the specific molecular steps that cause leukemia," says Hall.
Researchers will also be able to try a battery of drugs that target the molecular pathways identified for this disease.
Importantly, there are many changes seen in ATLL that are common to different forms of leukemia, something that should open up new therapeutic targets against other types of leukemia.
"We know these pathways are common in other leukemias. It offers a fantastic opportunity first to develop targeted drugs, but this model will also allow us to identify the molecular steps we see in other leukemias," says Hall.