Research for eradication of CML stem/progenitor cells which resisted Abl kinase inhibitors

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 17590987
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: OHNISHI Kazunori University Hospital, Professor, 医学部附属病院, 教授 (80252170)
• Co-Investigator(Kenkyū-buntansha): NAKAMURA Satoki University Hospital, Assistant Professor, 医学部附属病院, 助手 (20377740) ; SHIGENO Kazuyuki Faculty of Medicine, Assistant Professor, 医学部, 助手 (50402251)
• Project Period (FY): 2005 – 2006
• Keywords: Abl kinase inhibitor / Chronic myelogenous leukemia / colony assay / PI3K inhibitor / Bcr-Abl gene

Research Abstract

Chronic myelogenous leukemia (CML) is characterized by the reciprocal chromosomal translocation (9: 22), which generates the Philadelphia (Ph) chromosome. This translocation generates a novel fusion gene, BCR-ABL, that encodes an approximately p210 protein with hyperactive tyrosine kinase activity. Bcr-Abl-expressing leukemia cells are highly resistant to apoptosis. Imatinib (STI571), an Abl kinase inhibitor, is a highly effective agent for patients with CML. However, a small percentage of these patients and most advanced-phase patients relapse on Imatinib therapy. It is poorly understood whether the Abl kinase inhibitors are able to eradicate CML progenitor or stem cells. In this study, we investigated the role of homeobox A10 (HOXA10) in CML cell lines and the hematopoietic progenitor cells derived from CML patients, and whether the regulation of HOXA10 eradicate Bcr-Abl+ hematopoietic stem/progenitor cells. The Abl kinase inhibitors and PI3K inhibitor, LY294002, induced the expression of HOXA10 in CML cell but not AML cells, and the HOXA10 induced in CML cells enhanced apoptosis. Moreover, the reduction of HOXA10 expression by siRNA in CML cells inhibited apoptosis by treatment with the Abl kinase inhibitors and LY294002. These results revealed that HOXA10 had an important role in induction of apoptosis by the Abl kinase inhibitors in CML cells. Finally, we demonstrated that the inhibition of HOXA10 expression by siRNA increased CFU-GEMM, BFU-E, and CFU-GM when the cells were treated with the combination of BMS354825 and LY294002 compared to control cells. These findings indicated that HOXA10 played a critical role in the committed colony-formation in CML. This study shows for the first time that the Abl kinase inhibitor and LY294002 induced HOXA10, and HOXA10 had an important role in apoptosis or cell growth inhibition in CML cells in vitro. The Abl kinase inhibitor and LY294002 significantly suppressed the committed colony formation in CML.