title: The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia.
abstract: 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 nonhyperdiploid, 16 in TEL-AML1-positive versus-negative, and 13 in E2A-rearranged versus germ-line 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 < .001). Multivariate analysis including known risk factors revealed that BCL2L13 expression was an independent prognostic factor (P = .011). The same trend was observed in a validation group of 92 children with ALL treated on a different protocol at St Jude (P = .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.
authors.affiliation: Department of Pediatric Oncology and Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
authors.forename: Amy
authors.initials: A
authors.lastname: Holleman
authors.forename: Monique L
authors.initials: ML
authors.lastname: den Boer
authors.forename: Renée X
authors.initials: RX
authors.lastname: de Menezes
authors.forename: Meyling H
authors.initials: MH
authors.lastname: Cheok
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.forename: Karin M
authors.initials: KM
authors.lastname: Kazemier
authors.forename: Gritta E
authors.initials: GE
authors.lastname: Janka-Schaub
authors.forename: Ulrich
authors.initials: U
authors.lastname: Göbel
authors.forename: Ulrike B
authors.initials: UB
authors.lastname: Graubner
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
mesh_terms: D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D019070:Cell Lineage; D002648:Child; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011003:Ploidies; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D012307:Risk Factors; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D016896:Treatment Outcome