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DNA Repair Gene’s Role in Acute Myeloid Leukaemia

Melbourne researchers have uncovered a key factor protecting against age-related DNA damage, providing important clues about how our body guards against cancer.

The discovery was made by identifying a rare genetic mutation in three patients with an unusual, early-onset form of acute myeloid leukaemia (AML). The patients all lacked a DNA repair protein called MBD4, which led to them accumulating DNA damage at a higher rate than normal – as though they were ageing prematurely.

“In this study, we identified AML samples from three patients that showed unusually high rates of methylation damage to the DNA,” said Dr Edward Chew of The Royal Melbourne Hospital. “DNA methylation has a role in fine-tuning gene activity, but it also makes DNA more susceptible to damage.

“When we sequenced the patients’ genomes, we discovered they all carried changes in the same gene, called MBD4. This gene encodes a protein that repairs methylation damage. The loss of MBD4 in these patients explained why their cells had not repaired the damage,” he said.

AML is typically a disease of older adults, with the majority of patients aged more than 70. “The three patients who lacked MBD4 were predisposed to accumulating high rates of methylation damage, which we believe led to them developing AML as young adults (around 30 years old),” Chew said.

Methylation damage accumulates as part of normal ageing, but this study highlighted a particularly strong link with blood cancers. “We were looking at extreme cases where young individuals had accumulated abnormally high levels of methylation damage, driving the development of AML unusually early in life,” said Dr Ian Majewski of the Walter and Eliza Hall Institute. “It was as though their cells were ageing prematurely. Our research pinpoints methylation damage more generally – even at lower levels – being an important contributor to the development of cancers. An important next step is to understand precisely why blood cells are at risk from this form of DNA damage.”

The research discovery relied on recent advances in the fields of genomics and computational biology. “One of the three AML samples we studied was collected in the 1990s,” Majewski said. “At that time, DNA sequencing was still cumbersome and expensive, and we still hadn’t completed the first human genome sequence. We were lucky that our colleagues in The Netherlands had the foresight to store this sample for future analysis.”