Infant acute lymphoblastic leukaemia and the mixed lineage leukaemia (MLL) gene

Infant acute lymphoblastic leukaemia and the mixed lineage leukaemia (MLL) gene

In modern medicine, treatment of paediatric acute lymphoblastic leukaemia (ALL) represents one of the many success stories, with significant improvements in event free and overall survival.

However, infant ALL is a heterogeneous group with distinct biological and clinical characteristics, which continues to be resistant to this success. Infant ALL represents 2-5% of paediatric ALL cases.

The most common genetic aberration in infant ALL involves the mixed lineage leukaemia (MLL) gene, located on chromosome 11q23, which is involved in up to 80% of cases. Most chromosomal rearrangements are associated with leukaemias of a particular lineage. However, 11q23 rearrangements are unique in that they occur in both ALL and acute myeloid leukaemia (AML), hence the term mixed lineage leukaemia.

Since discovery of the MLL gene in 1992, its recombinome has been the subject of significant scientific research. There have been > 100 translocation partner genes identified, many of which have been characterized at the molecular level. MLL-EPS15/AF1P, t(1;11)(p32;q23) is a rare fusion, with a paucity of cases reported in the literature.

We have recently reported infant monozygotic twins harbouring the t(1;11)(p32;q23) translocation which we are studying to obtain further evidence regarding the pathogenesis of this disease.

Molecular analysis and sequencing has confirmed the breakpoint as a novel translocation breakpoint between the MLL and EPS15 genes and we are continuing to analyse the features at the genomic level. DNA analysis using Affymetrix 2.7M Cytogenetic Arrays has provided evidence for additional copy-number variations affecting the leukaemias in both twins, challenging the concept that a single genetic defect is sufficient for overt disease in infant MLL.

The identification of additional genetic abnormalities in such cases may provide opportunities for the development of novel targeted therapies in this disease.

This work is supported by the Children's Leukaemia and Cancer Research Foundation, WA, and the Whiteman Fellowship.