Biologic pathways associated with relapse in childhood acute lymphoblastic leukemia: a Children's Oncology Group study

Abstract

Outcome for children with childhood acute lymphoblastic leukemia (ALL) who relapse is poor. To gain insight into the mechanisms of relapse, we analyzed gene-expression profiles in 35 matched diagnosis/relapse pairs as well as 60 uniformly treated children at relapse using the Affymetrix platform. Matched-pair analyses revealed significant differences in the expression of genes involved in cell-cycle regulation, DNA repair, and apoptosis between diagnostic and earlyrelapse samples. Many of these pathways have been implicated in tumorigenesis previously and are attractive targets for intervention strategies. In contrast, no common pattern of changes was observed among late-relapse pairs. Earlyrelapse samples were more likely to be similar to their respective diagnostic sample while we noted greater divergence in gene

Genome-wide expression analysis of paired diagnosis–relapse samples in ALL indicates involvement of pathways related to DNA replication, cell cycle and DNA repair, independent of immune phenotype

“…2,[5][6][7]13,[35][36][37] Relatively few studies have focused on relapse samples and we are aware of only three previous studies using matched diagnosis-relapse pairs to better understand the process of relapsed ALL. 5,6,18 One of these studies was a small pilot study we performed a few years ago using seven patient pairs; 18 the other two are larger studies, one Australian (Beesley et al 5 ) and the other American (Bhojwani et al 6 ), who studied 11 and 35 matched diagnosis-relapse samples, respectively, and additional diagnosis samples. Although both seminal studies were performed carefully, they found only small numbers of genes to be differentially expressed between diagnosis and relapse samples, in general with changes that were relatively small (1.5-to 2-fold per gene), which are not easily interpreted in terms of mechanisms underlying the relapse process.…”

“…[8][9][10][11][12][13][14][15][16][17][18] Microarray technology can also provide an unbiased means to identify genes involved in the emergence of resistant leukemic clones. [5][6][7] For the identification of molecular mechanisms involved in relapse of ALL, pairwise comparison of matched diagnosis and relapses is, in principle, the most straightforward way to identify such genes. Several groups, including ours, have previously conducted such analyses.…”

“…Several groups, including ours, have previously conducted such analyses. 5,6,18 Surprisingly, the number of significantly differentially expressed genes identified was relatively small and changes in expression level between diagnosis and relapse were relatively small and only a handful of such genes were found, making it hard to interpret what biological mechanisms underlie the occurrence of relapse. Furthermore, only a minimal overlap was found between the gene sets identified in these studies.…”

“…Furthermore, only a minimal overlap was found between the gene sets identified in these studies. Given the solid efforts conducted before by other laboratories, [5][6][7] it became apparent that the question of which changes in gene expression are related to relapse in ALL was not an easy one to tackle.…”

The Fat1 cadherin is overexpressed and an independent prognostic factor for survival in paired diagnosis–relapse samples of precursor B-cell acute lymphoblastic leukemia

“…For preB-ALL, two recently published array sets 25,26 with matched pediatric diagnosis --relapse patients were analyzed. The use of matched diagnosis --relapse samples affords several advantages over a conventional cohort; it not only lends itself to the identification of genetic pathways and molecular mechanisms involved in relapse but also provides insights into the origins of the relapsed clone.…”