While overall survival rates for children with leukaemia have now reached 90%, certain subsets of patients experience much lower survival. In MLLr leukaemia, a gene called the MLL (Mixed Lineage Leukaemia) gene fuses with one of a range of other known genes on other chromosomes, driving the formation of a fast-growing cancer. Three-quarters of infants (babies under 12 months) with leukaemia have this high risk subtype. An international research collaboration we’re part of recently analysed data from the leukaemia cells of 2,345 MLLr patients worldwide and made some important discoveries.
Our Minimal Residual Disease (MRD) group, and 40 other laboratories world-wide led by the Goethe University in Frankfurt have just published research on the genetic changes in MLLr leukaemia. This article in the prestigious journal Leukemia follows up earlier reports by the same international collaborative group in 2009 and 2013. It provides an unprecedented insight into the genetics and biology of MLLr leukaemia, paving the way for the search for new, targeted treatments.
“This . . . opens up avenues for developing new, targeted drugs to kill leukaemia cells without damaging normal cells.”
Associate Professor Rosemary Sutton, Group Manager of the MRD group, noted that MLLr leukaemia often starts before birth and is highly aggressive, with scientists labelling it a ‘one-hit’ disease.
“Where most cancers are thought to be caused by two or more genetic changes, MLLr leukaemia probably arises from just one critical change,” she said.
Translocation and MLLr leukaemia
A genetic change called a translocation is the defining characteristic of MLLr leukaemia. In fact, the ‘r’ in MLLr stands for ‘rearranged’, referring to the rearrangement of specific genes.
All human cells, except sperm and ova, have 23 pairs of chromosomes, which carry all our different genes. Sometimes, in a particular cell, the ends of two chromosomes are damaged and break off but may reattach to the ‘wrong’ chromosome. This is known as a reciprocal translocation.
Often translocations aren’t a problem, but occasionally they fuse parts of two genes that form a destructive partnership. In MLLr leukaemia, a gene called the MLL (Mixed Lineage Leukaemia) gene fuses with one of a range of other known genes on other chromosomes, driving the formation of a fast-growing cancer.
Homing in on MLLr leukaemia
The study has:
- developed an improved technique for analysing MLLr patient samples. Our MRD group has been using a standard assay for many years to detect tiny numbers of leukaemia cells remaining after treatment (known as minimal residual disease). However the standard assay doesn’t work well for the MLLr subtype. This improved technique, which looks specifically at the MLL rearrangement, is more reliable, and will help improve patient treatment.
- improved understanding of the genetic features of MLLr leukaemia in different age groups. The break in the MLL gene doesn’t always happen in the same place. The study found that in infants with MLLr Acute Lymphoblastic Leukaemia, the breakpoint occurs further down the MLL gene than it does in older patients. Infants with this disease tend to do worse. This finding offers a possible reason why.
- increased researchers’ knowledge of the biological processes that drive proliferation of MLLr leukaemia cells. This research has brought to 94 the total number of MLL gene fusion partners identified so far. Interestingly however, in more than 90% of cases, only nine specific gene fusions occur.
“These nine fusions produce proteins that all activate a common cell growth pathway,” says A/Prof Sutton.
“This is exciting because it opens up avenues for developing new, targeted drugs to kill leukaemia cells without damaging normal cells.”
Our contribution to this unique multi-country study was supported by Sporting Chance Cancer Foundation and the Reuben Pelerman Benevolent Foundation.
Read the research paper ‘The MLL recombinome of acute leukemias in 2017‘ in the journal Leukemia.
Top image: Three-quarters of infants (babies under 12 months) with leukaemia have a high risk subtype called MLL-rearranged (MLLr) leukaemia. Image: istock