Distinct gene expression profiles determine molecular treatment response in childhood acute lymphoblastic leukemia.
Treatment resistance, as indicated by the presence of high levels of minimal residual disease (MRD) after induction therapy and induction consolidation, is associated with a poor prognosis in childhood acute lymphoblastic leukemia (ALL). We hypothesized that treatment resistance is an intrinsic feature of ALL cells reflected in the gene expression pattern and that resistance to chemotherapy can be predicted before treatment. To test these hypotheses, gene expression signatures of ALL samples with high MRD load were compared with those of samples without measurable MRD during treatment. We identified 54 genes that clearly distinguished resistant from sensitive ALL samples. Genes with low expression in resistant samples were predominantly associated with cell-cycle progression and apoptosis, suggesting that impaired cell proliferation and apoptosis are involved in treatment resistance. Prediction analysis using randomly selected samples as a training set and the remaining samples as a test set revealed an accuracy of 84%. We conclude that resistance to chemotherapy seems at least in part to be an intrinsic feature of ALL cells. Because treatment response could be predicted with high accuracy, gene expression profiling could become a clinically relevant tool for treatment stratification in the early course of childhood ALL.
Cario
Gunnar
G
Department of Pediatric Hematology and Oncology, Institute for Cell and Molecular Pathology, Hannover Medical School, Germany.
Stanulla
Martin
M
Fine
Bernard M
BM
Teuffel
Oliver
O
Neuhoff
Nils V
NV
Schrauder
André
A
Flohr
Thomas
T
Schäfer
Beat W
BW
Bartram
Claus R
CR
Welte
Karl
K
Schlegelberger
Brigitte
B
Schrappe
Martin
M
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007223:Infant; D008297:Male; D018365:Neoplasm, Residual / Q000188:drug therapy / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis
D000970:Antineoplastic Agents