Faculty Bibliography

The recent sequencing of the human genome and technical breakthroughs now make it possible to simultaneously determine mRNA expression levels of almost all of the identified genes in the human genome. DNA 'chip' or microarray technology holds great promise for the development of more refined, biologically-based classification systems for childhood ALL, as well as the identification of new targets for novel therapy. To date gene expression profiles have been described that correlate with subtypes of ALL defined by morphology, immunophenotype, cytogenetic alterations, and response to therapy. Mechanistic insights into treatment failure have come from the definition of mRNA signatures that predict in vitro chemoresistance, as well as differences between blasts at relapse and new diagnosis. New bioinformatics tools optimize data mining, but validation of findings is essential since 'over-fitting' the data is a common danger. In the future, genomic analysis will be complemented by evaluation of the cancer proteome

In the field of oncology, a growing emphasis is now being placed on individualizing treatment in a way that maximizes chance for cure while minimizing unwanted side effects. In childhood acute lymphoblastic leukemia (ALL), several well-established clinical and biologic prognostic variables have traditionally been used to risk stratify therapy for individual patients. While this approach has been very successful, many relapses still occur unpredictably in patients characterized as having favorable features of their disease at diagnosis. Furthermore, it is likely that other children are overtreated. Therefore, current initiatives in childhood leukemia have focused on identifying new prognostic markers to refine treatment decision-making. Recent advances, which include the sequencing of the human genome, and technical developments in high-throughput genomics and proteomics, have facilitated these efforts. This review will chart the evolution of individualized therapy for ALL, the most common malignancy of children.

Childhood acute lymphoblastic leukemia is one of the most curable of all human cancers, but new approaches are urgently needed for children who relapse and to avoid severe side effects of curative therapy. Work from the laboratories of Rob Pieters and William Evans, including a paper in this issue of Cancer Cell, has led to the identification of genes whose expression correlates with drug crossresistance and long term outcome. The goal is now to integrate these and other findings using gene expression technology into the care of children with the most common pediatric malignancy