Transcription suppression of SARI (suppressor of AP-1, regulated by IFN) by BCR-ABL in human leukemia cells.

The BCR-ABL tyrosine kinase has been implicated in the dysregulation of oncogenes and tumor suppressor genes involved in chronic myelogenous leukemia (CML). Suppressor of activator protein-1, regulated by interferon (SARI), is a recently identified tumor suppressor gene whose expression has been reported to be suppressed in several malignant neoplasms. However, the expression of SARI in leukemia and the underlying regulatory mechanism remain elusive. In this study, we demonstrated that SARI mRNA expression was low in CML patients. In vitro, BCR-ABL kinase inhibitor imatinib mesylate or siRNA specific to BCR-ABL upregulated SARI mRNA expression in human leukemia cells. In addition, JAK/STAT signaling inhibitor AG490 and RAS/MAPK signaling inhibitor PD98059 upregulated SARI mRNA expression, but PI3K/AKT pathway inhibitor LY294002 had no such effect. Functionally, silencing of SARI in CML-derived cell line K562 partially decreased imatinib mesylate-induced apoptosis. Taken together, these data demonstrate that SARI mRNA expression is suppressed by BCR-ABL through the downstream signaling pathways, suggesting SARI as a potential therapeutic target in CML.