Identification of genes associated with chemotherapy crossresistance and treatment response in childhood acute lymphoblastic leukemia.
Acute lymphoblastic leukemia (ALL) can be cured with combination chemotherapy in over 75% of children, but the cause of treatment failure in the remaining patients is unknown. We determined the sensitivity of ALL cells to individual antileukemic agents in 441 patients and used a genome-wide approach to identify 45 genes differentially expressed in ALL exhibiting crossresistance to prednisolone, vincristine, asparaginase, and daunorubicin. We also identified a distinct phenotype of discordant resistance to asparaginase and vincristine and 139 genes whose expression was associated with this novel phenotype. The expression of these genes discriminated treatment outcome in two independent patient populations, identifying a subset of patients with a markedly inferior outcome (37% +/- 13% 5 year DFS).
Lugthart
Sanne
S
Hematological Malignancy Program, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Cheok
Meyling H
MH
den Boer
Monique L
ML
Yang
Wenjian
W
Holleman
Amy
A
Cheng
Cheng
C
Pui
Ching-Hon
CH
Relling
Mary V
MV
Janka-Schaub
Gritta E
GE
Pieters
Rob
R
Evans
William E
WE
D000367:Age Factors; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001215:Asparaginase / Q000494:pharmacology / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D016000:Cluster Analysis; D050676:Core Binding Factor Alpha 2 Subunit; D003630:Daunorubicin / Q000494:pharmacology / Q000627:therapeutic use; D018572:Disease-Free Survival; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D015122:Mercaptopurine / Q000494:pharmacology; D009364:Neoplasm Recurrence, Local; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011237:Predictive Value of Tests; D011239:Prednisolone / Q000494:pharmacology / Q000627:therapeutic use; D025341:Principal Component Analysis; D016016:Proportional Hazards Models; D014178:Translocation, Genetic / Q000235:genetics; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology / Q000627:therapeutic use; D000097764:ETS Translocation Variant 6 Protein
D000970:Antineoplastic Agents; D001215:Asparaginase; D050676:Core Binding Factor Alpha 2 Subunit; D003630:Daunorubicin; D018398:Homeodomain Proteins; D015122:Mercaptopurine; D015514:Oncogene Proteins, Fusion; D011239:Prednisolone; D014750:Vincristine; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein; C089847:E2A-Pbx1 fusion protein