Establishment of novel differentiation-inducing therapy for leukemia with hematopoietic growth factors and arsenic trioxide

造血生长因子和三氧化二砷新型白血病诱导分化疗法的建立

• 批准号: 13671083
• 负责人: KIZAKI Masahiro
• 金额: $ 2.62万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671083/
• 关键词: Arsenic trioxide; Cytokine; Leukemia; GM-CSF; Apoptosis; BMP; Myeloma; Differentiation; 造血因子; ヒ素; 細胞分化; マウスモデル; Jak2キナーゼ

Arsenic trioxide (As_2O_3) effectively induces clinical remission via apoptosis in related acute promyelocytic leukemia (APL). However, because this new anti-leukemic drug is also considered to be a poison, its possible adverse effects are a highly important issue related to its clinical use. We investigated both in vitro and in vivo, the effects of a combination of As_2O_3 and GM-CSF as a novel therapeutic approach for the treatment of acute leukemia. Treatment of acute lmyeloid eukemic cells with a combination of As_2O_3 and GM-CSF for 4 days resulted in differentiation, but not apoptosis, to mature granulocytes. GM-CSF was found to be associated with increased tyrosine phosphorylation of Jak2 kinase in acute promyelocytic leukemia (APL) cells, and a specific inhibitor of Jak2, AG490, completely blocked the ability of GM-CSF to prevent apoptosis and induce differentiation of As_2O_3-treated APL cells. In in vivo analysis, As_2O_3 induced differentiation of APL cells in a retinoic aci … More d-resistant APL model of human GM-CSF-producing transgenic SCID mice that had a high level of human GM-CSF in their sera. In contrast, As_2O_3 alone diminished tumors in retinoic acid-resistant APL UF-1 cells transplanted into NOD/SCID mice via induction of apoptosis.We also performed the experiments using TGF-β superfamily cytokines including bone morphogenetic protein(BMP) and activin A for inducing apoptosis of leukemia and myeloma cells. BMP induces apoptosis of human myeloma cell lines and primary samples. BMP caused cell cycle arrest in the G1 phase which was associated with accumulation of p21 and p27, and the subsequent apoptosis of myeloma cells. BMP also induced down-regulation of Bcl-X_L through the inactivation of STAT3, resulting in the induction of apoptosis of myeloma cells. In addition, activin A induced rapid apoptosis of chronic myeloid leukemia (CML) cells via transient induction of Mcl-1. These results suggest that cytokines may have a potential to be novel therapeutic agents for treatment in patients with leukemia and myeloma. Especially, a combination of As_2O_3 and GM-CSF appears to be a novel differentiation-inducing therapy for APL with less toxic effects. Less

砷三氧化物（AS_2O_3）有效地通过相关急性临床前临床白血病（APL）有效地诱导临床缓解。但是，由于这种新的抗白血病药物也被认为是毒药，因此其可能的不良影响是与其临床使用相关的非常重要的问题。我们研究了体外和体内，AS_2O_3和GM-CSF的组合作为治疗急性白血病的一种新型治疗方法。用AS_2O_3和GM-CSF的组合处理急性Lmyeloid Eukemia细胞4天，导致分化，但没有细胞凋亡，从而使成熟的粒细胞分化。发现GM-CSF与JAK2激酶在急性前临床白血病（APL）细胞中的酪氨酸磷酸化增加以及JAK2 AG490的特定抑制剂有关，完全阻断了GM-CSF的能力，可预防AS_2O_3-3-饮食APL细胞的细胞凋亡和影响AS_2O_2O_3-摄取的APL细胞的分化。在体内分析中，AS_2O_3诱导了视黄型ACI中APL细胞的分化…在其血清中具有很高水平的人GM-CSF的人GM-CSF产生的人GM-CSF的抗性APL模型。相反，单独的AS_2O_3通过诱导凋亡诱导将视黄酸APL UF-1细胞减少了耐药性APL UF-1细胞。我们还使用TGF-β超家族细胞因子（包括骨形成蛋白（BMP）和激活A型垂体症）进行了TGF-β超家族细胞因子（包括骨形成蛋白（BMP）和激活的嗜地症）的实验。 BMP诱导人骨髓瘤细胞系和主要样品的凋亡。 BMP在G1期导致细胞周期停滞，这与P21和P27的积累以及随后的骨髓瘤细胞凋亡有关。 BMP还通过灭活STAT3诱导了BCL-X_L的下调，从而导致骨髓瘤细胞凋亡诱导。此外，激活素A通过瞬时诱导MCL-1诱导的慢性髓样白血病（CML）细胞的快速凋亡。这些结果表明，细胞因子可能有可能成为白血病和骨髓瘤患者治疗的新型治疗剂。尤其是，AS_2O_3和GM-CSF的组合似乎是一种新型的诱导毒性疗法的新型毒性疗法。较少的

项目成果

Takayama N, Kizaki M, et al.: "A novel mutation of PML/RARα chimeric gene exhibits dramatically decreased ligand-binding activity and confers acquired resistance to RA in APL"Exp. Hematol.. 29. 864-872 (2001)

Takayama N、Kizaki M 等人：“PML/RARα 嵌合基因的一种新突变表现出显着降低的配体结合活性，并赋予 Hematol 获得性 RA 抗性”Exp. 29. 864-872 (2001)

Fukuchi Y, Kizaki M, et al: "Mcl-1, an early-induction molecule, modulates activin A-induced apoptosis and differentiation of CML cells"Oncogene. 20(6). 704-713 (2001)

Fukuchi Y、Kizaki M 等人：“Mcl-1，一种早期诱导分子，调节激活素 A 诱导的 CML 细胞凋亡和分化”癌基因。

Hirano T, Kizaki M, Kato K, et al.: "Enhancement of sensitivity by bestatin of acute promyelocytic leukemia NB4 cells to all-trans retinoic acid"Leuk. Res.. 26(12). 1097-1103 (2002)

Hirano T、Kizaki M、Kato K 等人：“急性早幼粒细胞白血病 NB4 细胞的贝他汀对全反式视黄酸的敏感性增强”Leuk。

Ito K, Kinjo K, Nakazato T, Ikeda Y and Kizaki M: "Expression and sequence analyses of p33^<ING1> gene in myeloid leukemia"American Journal of Hematology. 69(2). 141-143 (2002)

Ito K、Kinjo K、Nakazato T、Ikeda Y 和 Kizaki M：“骨髓性白血病中 p33^<ING1> 基因的表达和序列分析”美国血液学杂志。

Ito K, Nakazato T, Miyakawa Y, Yamato K, Ikeda Y, Kizaki M: "Caffeine induces G_2/M arrest and apoptosis via novel p53-dependent pathway in NB4 promyelocytic leukemia cells"Journal of Cellular Physiology. (in press).

Ito K、Nakazato T、Miyakawa Y、Yamato K、Ikeda Y、Kizaki M：“咖啡因在 NB4 早幼粒细胞白血病细胞中通过新型 p53 依赖性途径诱导 G_2/M 停滞和细胞凋亡”《细胞生理学杂志》。