A genome-wide view of the in vitro response to l-asparaginase in acute lymphoblastic leukemia.
To investigate the effect of l-asparaginase on acute lymphoblastic leukemia (ALL), we used cDNA microarrays to obtain a genome-wide view of gene expression both at baseline and after in vitro exposure to l-asparaginase in cell lines and pediatric ALL samples. In 16 cell lines, a baseline gene expression pattern distinguished l-asparaginase sensitivity from resistance. However, for 28 pediatric ALL samples, no consistent baseline expression pattern was associated with sensitivity to l-asparaginase. In particular, baseline expression of asparagine synthetase (ASNS) was not predictive of response to l-asparaginase. After exposure to l-asparaginase, 5 cell lines and 10 clinical samples exhibited very similar changes in the expression of a large number of genes. However, the gene expression changes occurred more slowly in the clinical samples. These changes included a consistent increase in expression of tRNA synthetases and solute transporters and activating transcription factor and CCAAT/enhancer binding protein family members, a response similar to that observed with amino acid starvation. There was also a consistent decrease in many genes associated with proliferation. Taken together, the changes seem to reflect a consistent coordinated response to asparagine starvation in both cell lines and clinical samples. Importantly, in the clinical samples, increased expression of ASNS after l-asparaginase exposure was not associated with in vitro resistance to l-asparaginase, indicating that ASNS-independent mechanisms of in vitro l-asparaginase resistance are common in ALL. These results suggest that targeting particular genes involved in the response to amino acid starvation in ALL cells may provide a novel way to overcome l-asparaginase resistance.
Fine
Bernard M
BM
Center for Molecular Biology in Medicine, Veterans Affairs Palo Alto Health Care System and Department of Medicine, Palo Alto, CA, USA.
Kaspers
Gertjan J L
GJ
Ho
Minh
M
Loonen
Anne H
AH
Boxer
Linda M
LM
D000293:Adolescent; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019677:Artificial Gene Fusion; D001215:Asparaginase / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002648:Child; D005260:Female; D015894:Genome, Human; D006801:Humans; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D012008:Recurrence; D014178:Translocation, Genetic
D000970:Antineoplastic Agents; D001215:Asparaginase