Biologic pathways associated with relapse in childhood acute lymphoblastic leukemia: a Children's Oncology Group study.
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 early-relapse 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. Early-relapse samples were more likely to be similar to their respective diagnostic sample while we noted greater divergence in gene-expression patterns among late-relapse pairs. Comparison of expression profiles of early- versus late-relapse samples indicated that early-relapse clones were characterized by overexpression of biologic pathways associated with cell-cycle regulation. These results suggest that early-relapse results from the emergence of a related clone, characterized by the up-regulation of genes mediating cell proliferation. In contrast, late relapse appears to be mediated by diverse pathways.
Bhojwani
Deepa
D
New York University (NYU) Cancer Institute and Division of Pediatric Hematology/Oncology, NY 10016, USA.
Kang
Huining
H
Moskowitz
Naomi P
NP
Min
Dong-Joon
DJ
Lee
Hokyung
H
Potter
Jeffrey W
JW
Davidson
George
G
Willman
Cheryl L
CL
Borowitz
Michael J
MJ
Belitskaya-Levy
Ilana
I
Hunger
Stephen P
SP
Raetz
Elizabeth A
EA
Carroll
William L
WL
D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D002648:Child; D002999:Clone Cells / Q000473:pathology; D004260:DNA Repair / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D016555:Matched-Pair Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology*; D012008:Recurrence; D013997:Time Factors