| Project/Area Number |
13470161
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Pediatrics
|
|---|
| Research Institution | University of Yamanashi (2003)
山梨医科大学 (2001-2002) |
|---|
Principal Investigator |
NAKAZAWA Shinpei University of Yamanashi, Interdisciplinary Graduate School of medicine and Engineering, Professor, 大学院・医学工学総合研究部, 教授 (90090034)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
GOI Kumiko University of Yamanashi, Hospital, Research Associate, 医学部附属病院, 助手 (70324192)
INUKAI Takeshi University of Yamanashi, Interdisciplinary Graduate School of medicine and Engineering, Research Associate, 大学院・医学工学総合研究部, 助手 (30293450)
SUGITA Kanji University of Yamanashi, Hospital, Assistant-Professor, 医学部附属病院, 講師 (60138055)
|
|---|
| Project Period (FY) |
2001 – 2003
|
| Project Status |
Completed (Fiscal Year 2003)
|
| Budget Amount *help |
¥7,100,000 (Direct Cost: ¥7,100,000)
Fiscal Year 2003: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2002: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 2001: ¥3,000,000 (Direct Cost: ¥3,000,000)
|
|---|
| Keywords | childhood leukemia / apoptosis / chemo-resistance / cell cycle / cytokine / TNF-family ligands / all-SCT / GVL effect / 白血病 / Philadelhia染色体陽性白血病 / 11q23転座型白血病 / T細胞型急性リンパ性白血病 / 造血因子 / STI571 / 耐性機序 / Philadelphia染色体陽性白血病 / HDAC inhibitor / 細胞周期停止 / 移植片対白血病(GVL)効果 / philadelphia染色体陽性白血病 / 11q23転座型急性リンパ性白血病 |
|---|
| Research Abstract |
Mechanisms of apoptosis have been well established and, subsequently, it is clarifying that resistance to apoptosis could be involved in leukemogenesis and resistance to chemotherapy. In this study, to identify new therapeutic approaches, we have analyzed the underlying mechanisms of resistance to apoptosis in poor prognostic acute lymphoblastic leukemia (ALL) such as Philadelphia chromosome (Ph1)-positive ALL and ALL with 11q23 translocations.
In Ph1-positive ALL, signaling pathways for growth and survival, which are tightly regulated with growth factors in normal hematopoietic progenitors, are persistently activated by BCR-ABL fusion tyrosine kinase. STI571, a specific inhibitor of BCR-ABL and a potent clinical agent for CML and Ph1-positive ALL, induces growth arrest and apoptosis of Ph1-positive leukemic cells by inactivating those signaling pathways. We have demonstrated that multiple growth factors rescue the growth and survival of STI571-treated Ph1-positive leukemic cells by act
… More
ivating the signaling pathways. IL-3, IL-5, and GM-CSF potently rescue myeloid Ph1-positive leukemic cells, while IL-7 and FLT3-L cooperatively rescue lymphoid Ph1-positive leukemic cells. These observations suggest that endogenous growth factors might antagonize the anti-leukemic effect of STI-571 in vivo. Since specific inhibitors for MAPK and PI3K efficiently induce growth arrest and apoptosis of STI571-treated Ph1-positive leukemic cells in the presence of growth factors, these agents could be enhance the anti-leukemic activity of STI-571. We have also demonstrated that HDAC inhibitors, such as TSA, and Jak2 inhibitor AG490 effectively induce growth arrest and apoptosis of Ph1-positive and translocations with 11q23 leukemic cell lines.
Moreover, we investigated that TRAIL, one of the cytotoxic ligands expressed on the surface of cytotoxic T lymphocytes, but not Fast efficiently induces apoptosis of Ph1-positive leukemias, suggesting that TRAIL rather than FasL plays an important role in GVL effect on Ph1-positive leukemias. In contrast, leukemia cell lines with 11q23 translocations were highly resistant to recombinant soluble TRAIL, suggesting that resistance to TRAIL could be one of the mechanisms for relatively poor outcome of allo SCT in patients with ALL with 11q23 translocations. 10. KEY WORDS Less
|
