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

根除对Abl激酶抑制剂有抵抗力的CML干/祖细胞的研究

基本信息

批准号：
17590987
负责人：
OHNISHI Kazunori
金额：
$ 2.24万
依托单位：
Hamamatsu University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

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.

慢性粒细胞白血病（CML）的特征是相互染色体易位（9：22），产生费城（Ph）染色体。这种易位产生了一种新的融合基因BCR-ABL，它编码一种具有高活性酪氨酸激酶活性的约p210蛋白。表达Bcr-Abl的白血病细胞对凋亡具有高度抗性。伊马替尼（Imatinib，STI 571）是一种Abl激酶抑制剂，对CML患者有很好的疗效。然而，这些患者中的一小部分和大多数晚期患者在伊马替尼治疗后复发。Abl激酶抑制剂是否能够根除CML祖细胞或干细胞尚不清楚。本研究探讨同源框A10（HOXA 10）在CML细胞系和CML患者造血祖细胞中的作用，以及HOXA 10的调控是否能根除Bcr-Abl+造血干/祖细胞。Abl激酶抑制剂和PI 3 K抑制剂LY 294002可诱导CML细胞HOXA 10的表达，而AML细胞则无此作用，诱导CML细胞HOXA 10的表达可促进细胞凋亡。此外，通过siRNA降低CML细胞中HOXA 10的表达，通过用Abl激酶抑制剂和LY 294002处理抑制了细胞凋亡。这些结果表明HOXA 10在Abl激酶抑制剂诱导CML细胞凋亡中具有重要作用。最后，我们证明了与对照细胞相比，当用BMS 354825和LY 294002的组合处理细胞时，通过siRNA抑制HOXA 10表达增加了CFU-GEMM、BFU-E和CFU-GM。这些结果表明HOXA 10在CML的定向集落形成中起关键作用。本研究首次发现Abl激酶抑制剂和LY 294002诱导了HOXA 10的表达，并且HOXA 10在体外CML细胞的凋亡或细胞生长抑制中具有重要作用。Abl激酶抑制剂和LY 294002显著抑制CML的定向集落形成。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Etodolac induces apoptosis and inhibits cell adhesion to bone marrow stromal cells in human myeloma cells.

DOI：
10.1182/blood.v104.11.4836.4836
发表时间：
2004-11
期刊：
Leukemia research
影响因子：
2.7
作者：
Satoki Nakamura;Miki Kobayashi;K. Shibata;N. Sahara;K. Shigeno;K. Shinjo;K. Naito;Hideharu Hayashi;K. Ohnishi
通讯作者：
Satoki Nakamura;Miki Kobayashi;K. Shibata;N. Sahara;K. Shigeno;K. Shinjo;K. Naito;Hideharu Hayashi;K. Ohnishi

Delayed recovery of normal hematopoiesis in arsenic trioxide treatment of acute promyelocytic leukemia:: A comparison to all-trans retinoic acid treatment