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Blood, 15 January 2006, Vol. 107, No. 2, pp. 769-776.
Prepublished online as a Blood First Edition Paper on September 27, 2005; DOI 10.1182/blood-2005-07-2930.
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Submitted July 21, 2005
Accepted September 14, 2005
The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia
Amy Holleman, Monique L den Boer*, Renee X Menezes, Meyling H Cheok, Cheng Cheng, Karin M Kazemier, Gritta E Janka-Schaub, Ulrich Gobel, Ulrike B Graubner, William E Evans, and Rob Pieters
Department of Pediatric Oncology and Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
Department of Pediatric Oncology and Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands; Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
COALL Study Group, Hamburg, Germany; Children's University Hospital, Hamburg, Germany
COALL Study Group, Hamburg, Germany; Department of Pediatric Oncology, University Medical Center, Heinrich-Heine-University, Dusseldorf, Germany
COALL Study Group, Hamburg, Germany; Department of Pediatric Oncology, Dr. von Haunersches Children's Hospital, University of Munich, Munich, Germany
* Corresponding author; email: m.l.denboer{at}erasmusmc.nl.
Childhood acute lymphoblastic leukemia (ALL) consists of various subtypes that respond differently to cytotoxic drugs and therefore have a markedly different clinical outcome. We used microarrays to investigate in 190 children with ALL at initial diagnosis whether 70 key apoptosis genes were differentially expressed between leukemic subgroups defined by lineage, genetic subtype, in vitro drug resistance and clinical outcome. The expression of 44 of 70 genes was significantly different in T- versus B-lineage ALL, 22 genes differed in hyperdiploid versus non-hyperdiploid, 16 in TEL-AML1 positive versus negative, and 13 in E2A-rearranged versus germline B-lineage ALL. Expression of MCL1 and DAPK1 was significantly associated with prednisolone sensitivity, whereas BCL2L13, HRK and TNF were related to L-asparaginase resistance. BCL2L13 overexpression was also associated with unfavorable clinical outcome (P< 0.001). Multivariate analysis including known risk factors revealed that BCL2L13 expression was an independent prognostic factor (P=0.011). The same trend was observed in a validation group of 92 children with ALL treated on a different protocol at St. Jude (P=0.051). In conclusion, ALL subtypes have a unique expression pattern of apoptosis genes and our data suggest that selective genes are linked to cellular drug resistance and prognosis in childhood B-lineage ALL.
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