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

Frank Staal, D (Dirk) de Ridder, Tomek Szczepanski, T (Tom) Schonewille, ECE van der Linden, ER van Wering, Vincent van der Velden, Jacques Dongen

Research output: Contribution to journalArticleAcademicpeer-review

39 Citations (Scopus)

Abstract

Almost a quarter of pediatric patients with acute lymphoblastic leukemia (ALL) suffer from relapses. The biological mechanisms underlying therapy response and development of relapses have remained unclear. In an attempt to better understand this phenomenon, we have analyzed 41 matched diagnosis-relapse pairs of ALL patients using genome-wide expression arrays (82 arrays) on purified leukemic cells. In roughly half of the patients, very few differences between diagnosis and relapse samples were found ('stable group'), suggesting that mostly extra-leukemic factors (for example, drug distribution, drug metabolism, compliance) contributed to the relapse. Therefore, we focused our further analysis on 20 sample pairs with clear differences in gene expression ('skewed group'), reasoning that these would allow us to better study the biological mechanisms underlying relapsed ALL. After finding the differences between diagnosis and relapse pairs in this group, we identified four major gene clusters corresponding to several pathways associated with changes in cell cycle, DNA replication, recombination and repair, as well as B-cell developmental genes. We also identified cancer genes commonly associated with colon carcinomas and ubiquitination to be upregulated in relapsed ALL. Thus, about half of the relapses are due to the selection or emergence of a clone with deregulated expression of genes involved in pathways that regulate B-cell signaling, development, cell cycle, cellular division and replication. Leukemia (2010) 24, 491-499; doi:10.1038/leu.2009.286; published online 14 January 2010
Original languageUndefined/Unknown
Pages (from-to)491-499
Number of pages9
JournalLeukemia
Volume24
Issue number3
DOIs
Publication statusPublished - 2010

Cite this