Comparative gene expression analysis of a chronic myelogenous leukemia cell line resistant to cyclophosphamide using oligonucleotide arrays and response to tyrosine kinase inhibitors
✍ Scribed by Fei Bao; Paula Polk; Mary L. Nordberg; Diana M. Veillon; Amanda Sun; Michael Deininger; David Murray; Borje S. Andersson; Reinhold Munker
- Publisher
- Elsevier Science
- Year
- 2007
- Tongue
- English
- Weight
- 471 KB
- Volume
- 31
- Category
- Article
- ISSN
- 0145-2126
No coin nor oath required. For personal study only.
✦ Synopsis
Acquired imatinib resistance in chronic myelogenous leukemia (CML) can be the consequence of mutations in the kinase domain of BCR-ABL or increased protein levels. However, as in other malignancies, acquired resistance to cytostatic drugs is a common reason for treatment failure or disease progression. As a model for drug resistance, we developed a CML cell line resistant to cyclophosphamide (CP). Using oligonucleotide arrays, we examined changes in global gene expression. Selected genes were also examined by real-time PCR and flow cytometry. Neither the parent nor the resistant lines had mutations in their ATP binding domain. Filtering genes with a low-base line expression, a total of 239 genes showed significant changes (162 up- and 77 down-regulated) in the resistant clone. Most of the up-regulated genes were associated with metabolism, signal transduction, or encoded enzymes. The gene for aldehyde dehydrogenase 1 was over-expressed more than 2000-fold in the resistant clone. BCR-ABL was expressed in both cell lines to a comparable extent. When exposed to the tyrosine kinase inhibitors imatinib and nilotinib, both lines were sensitive. In conclusion, we found multiple genetic changes in a CML cell line resistant to CP related to metabolism, signal transduction or apoptosis. Despite these changes, the resistant cells retained sensitivity to tyrosine kinase inhibitors.