New thinking on why childhood leukaemia develops

Why does a one year old, a three year old or ten year old get leukaemia?

This is the question Dr Ian Morison, Cancer Genetics Laboratory researcher and his team at the University of Otago ask themselves every day.

Are all children equally at risk or not?

With help from the Child Cancer Foundation and the Cancer Society, the team's collaborative research with paediatric oncologists throughout New Zealand has begun to find some answers. In their recently published research in the prestigious American medical journal "Blood", non- hereditary genetic effects may be predisposing children to Acute Lymphoblastic Leukaemia (ALL) "before they are even conceived", says Dr Morison.

All cancers are due to damage to the genes of a single cell, which then divides and grows out of control, says Dr Morison. Every cell in the body has two copies of every gene, and many of these are used to slow down cell growth.

We now have evidence that one of the two copies of a critical growth control gene is turned off before conception: a developing bone marrow cell might be like a car coming off the production line without a hand brake. The burning question now is why? Is this a mistake or part of the design?

"After adding our discovery to the mounting overseas evidence that the disease begins before birth, I believe we can start to reassure worried parents because it seems unlikely that their children's exposure to cell phone towers, high voltage power wires, or any other environmental factor has any bearing whatsoever on their chances of developing the disease," says Dr Morison. The team at Otago analysed DNA from over 60 affected New Zealand families and found that the genetic damage affecting developing lymphoblasts (blood cells) was "occurring overwhelmingly on the maternal copy of the involved gene."

This discovery indicates that the corresponding paternal copy has been inactivated, preventing it from acting as an effective backup (i.e. the missing handbrake), suggesting that the predisposition may go right back to before conception, he says.

Dr Morison says they are already making good progress on the next step which is finding out more about why the paternal copy of the gene is inactivated.

Director of the Cancer Genetics Laboratory, Professor Tony Reeve says further research into the critical early events in the disease is crucial to understanding and preventing childhood leukaemia.

'it is important to take a step back and further investigate the biology of the disease and then start looking for the causes. By identifying the precise nature of damage to the lymphoblast we can start to understand what caused it and when it occurred," he said.

Sharing Autumn 2002

Further Otago Research

Dr Ian Morison's research into the causes of childhood leukaemia at the University of Otago Medical School involved a project financed by the Child Cancer Foundation's Otago/Southland Division.

Josh Ramsay, who was supervised by Dr Morison, was attempting to clarify the role of imprinted genes in human cancers and other diseases.

A small proportion of genes are affected by a process called imprinting. One or other parent "imprints" some of their genes in a way that the copy they pass on is "silenced". For example, for IGF22, a gene involved in childhood kidney tumours, only the copy from Dad is active, whereas Mum's copy is silent.

H19, on the other hand, a gene involved in some childhood cancers, is silenced by Dad while Mum's copy is active.

Previously the Cancer Genetics Laboratory where Josh worked gained world wide attention when it showed abnormal imprinting of IGF2 in kidney cancer (Wilms).

A puzzle surrounding imprinting is why it occurs at all where there is clear evidence that disruption of imprinting can cause cancer and other conditions.

Josh collated information about imprinted genes from humans and mice in order to clarify exactly which genes are imprinted. From 100 to 30,000 genes are affected by imprinting.

The Otago group will publish Josh's work in an international medical journal and believe that it will form a solid basis for future studies on imprinted genes in cancer.

Dr Ian Morison maintains a website of imprinted genes at igc.otago.ac.nz

Sharing Summer 2004