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A Genome-Wide View of the In vitro Response to L-Asparaginase in Acute Lymphoblastic Leukemia

¹ Center for Molecular Biology in Medicine, Veterans Affairs Palo Alto Health Care System and Department of Medicine; ² Department of Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California and ³ Pediatric Hematology/Oncology, VU University Medical Center, Amsterdam, the Netherlands

Request for reprints: Linda M. Boxer, Division of Hematology, Stanford University School of Medicine, 269 Campus Drive, CCSR 1155, Stanford, CA 94305-5156. Phone: 650-849-0551; Fax: 650-858-3982; E-mail: lboxer{at}stanford.edu.

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.

Key Words: asparaginase • acute lymphoblastic leukemia • expression profiling • microarrays

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