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Infection link to leukaemia

Wednesday 1 April 2009

“Scientists have shown how common infections might trigger childhood leukaemia,” BBC News reported. It said that scientists have identified a molecule that is produced in response to infection, but also appears to trigger the multiplication of pre-cancerous stem cells at the expense of healthy cells. The BBC said that this suggests that common infections may trigger childhood leukaemia.

This laboratory study examined the effects of TGF-β on a group of developing white blood cells with a mutation that predisposes them to develop into lymphoblastic leukaemic cells. These cells cause the disease acute lymphoblastic leukaemia (ALL) – the most common childhood leukaemia.

These findings are valuable to medical researchers, but whether or not the TGF- β generated during infections plays a role in the development of leukaemia needs further study. It is not possible to link the production of TGF-β, a general component of the immune system, to a particular ‘bug’, as suggested by the Daily Express headline. Therefore it is unclear how a vaccine against ALL could be developed.

Where did the story come from?

Anthony M. Ford from The Institute of Cancer Research in Surrey, and colleagues from other academic institutions in Italy and Spain, carried out this research. The study was funded by the Leukaemia Research Fund UK, the Kay Kendell Leukaemia Fund UK, and several other funds and organisations in Italy and Spain. The study was published in the peer-reviewed medical journal Journal of Clinical Investigation .

What kind of scientific study was this?

Childhood acute lymphoblastic leukaemia (ALL) is the most common type of leukaemia in children. It has been linked to a chromosomal alteration, which leads to the abnormal joining of two genes to form a “fusion” gene called the TEL-AML (or ETV6-RUNX1) “fusion” gene. The TEL-AML1 protein, coded for by this gene, generates and may maintain pre-leukaemic clones (groups of early cells that can develop into leukaemic cells).

However, this protein is not solely responsible for the  development of ALL because only about 1% of individuals who have the mutation go on to develop the disease. Therefore, it is thought that further genetic changes must occur, which allows the disease to develop. Some studies have suggested that infections may play a role in converting the cells from the pre-leukaemic to leukaemic stage.

This laboratory study looked at the development of immune cells from mice and human umbilical cords. The researchers were specifically interested in whether the protein TGF-β might affect precursor white blood cells carrying the TEL-AML1 gene. TGF-β is one of the key components of the immune system that is produced during infection, and is known to affect how early B cell progenitors develop. B cells are a group of lymphocytes that are involved in the immune response. There are two types of lymphocytes – B and T – and the B cell line is most frequently affected in ALL.

The researchers aimed to investigate whether TGF-β affected early B cell lines that expressed the TEL-AML1 gene differently to those that did not express the mutated gene.

In their first experiment, the researchers used a mouse cell line that is thought to be able to develop into B cells. They introduced the TEL-AML1 gene into some of these cells and looked at how this affected their division to form new cells compared to normal cells. They then looked at the effects of adding the TGF-β protein to both types of cells in the laboratory, and compared this with normal cells. The researchers also looked at what biochemical pathways might be involved in these differences.

In their second set of experiments, the researchers took bone marrow cells (including B cell progenitors) from mice genetically engineered to carry the TEL-AML1 gene and normal mice. They grew these cells in the laboratory, exposed them to TGF-β and looked at the effect on cell division.

Finally, the researchers introduced the TEL-AML1 gene into human umbilical cord cells. They grew these cells in the laboratory to determine what proportion would develop into the type of cells thought to be pre-leukaemic. They repeated this experiment in the presence of TGF-β to see whether the proportion of pre-leukaemic cells would change.

What were the results of the study?

The researchers found that in mice, the early B lymphocyte cells that contained the TEL-AML1 gene divided more slowly than those that did not contain the gene. However, when they added TGF-β to the cells, this slowed the division of the normal cells but not of the cells with the TEL-AML1 gene. This meant that the two groups of cells now divided at roughly the same rate.

The researchers found similar results with white blood cell precursor cells taken from the bone marrow of normal mice and mice genetically engineered to carry the TEL-AML1 gene. When these cells were grown in the laboratory, adding TGF-β protein to the cells from normal mice slowed their division, but did not affect the division of cells from the genetically engineered mice, as expected.

Also, it was demonstrated that introducing the TEL-AML1 gene into human umbilical cord cells could lead to the generation of a group of pre-leukaemic early B cells (that could go on to develop into leukaemic cells). Adding TGF-β increased the proportion of these pre-leukaemic cells.

What interpretations did the researchers draw from these results?

The researchers conclude that their results demonstrate a possible way in which the immune response to infection could promote the malignant (cancerous) development of TEL-AML1–expressing pre-leukaemic clones.

What does the NHS Knowledge Service make of this study?

This research aimed to investigate how a genetic mutation that leads to the development of early leukaemic cells may be influenced by the presence of TGF-β, which is produced during infections. The research suggests a mechanism by which the division of early leukaemic cells is supported by the presence of the TGF-β protein.

The findings are valuable to the medical and scientific world in furthering the understanding of how genetic and immune factors can interact and lead to the development of cancerous conditions. However, further research in animals will be needed to confirm that TGF-β generated in the presence of infection actually plays a role in the development of leukaemia.

The practical implications of these findings are unclear at present. It is not possible to link the production of TGF-β, a general component of the immune system, to a particular ‘bug’, as headlined by the Daily Express . Therefore, it is unclear whether a “vaccine” against leukaemia would be possible as it would have to target specific infectious agents.

The causes of childhood leukaemia remain uncertain, but suggested triggers include genetic factors, and environmental triggers, such as radiation, chemical exposure and possibly a range of infections.

Analysis by Bazian
Edited by NHS Website

Links to the headlines

Leukaemia link to bug raises hopes of vaccine.

Daily Express, 1 April 2009

How infection may spark leukaemia.

BBC News, 1 April 2009

Links to the science

Ford AM, Palmi C, Bueno C, et al.

The TEL-AML1 leukemia fusion gene dysregulates the TGF-β pathway in early B lineage progenitor cells.

Journal of Clinical Investigation 2009; published March 16